Current Drug Metabolism, 2006, 7, 23-37 23

Cytochrome P450 and Anticancer Drugs

Ken-ichi Fujita*

Department of Clinical Oncology, Saitama medical school, 38 Morohongou, Moroyama-cho, Iruma-gun, 350-0495,
Japan

Abstract: Cytochrome P450 (CYP) is involved in the metabolism of a variety of anticancer drugs. CYP activities are
known to be modified by several factors including genetic polymorphisms, changes in physiological conditions such as
age, disease status or intake of certain drugs or foods or environmental factors such as smoking. These factors may cause
interindividual differences in the pharmacokinetic profiles of anticancer drugs, leading to the variations of efficacy or
toxicity of the drugs.
Genetic polymorphisms present in CYPs sometimes result in the reduced activity of the enzymes causing low metabolic
clearance of drugs or low production of active metabolites. For example, the formation of endoxifen, which is an active
metabolite of tamoxifen, was less in patients with inactive polymorphic CYP2D6 than those with the wild type enzyme.
CYP3A is the most abundant CYP expressed in the human liver and the small intestine that is involved in the metabolism
of various anticancer drugs. The catalytic activity of CYP3A shows a large interindividual variability giving rise to large
interindividual differences in the pharmacokinetic profiles of some anticancer drugs. So far, many attempts have been
made to monitor the phenotypic activity of CYP3A in order to reduce the pharmacokinetic variations of anticancer drugs.
Erythromycin, midazolam and cortisol are commonly used to monitor in vivo hepatic CYP3A activity. These methods
have been applied to reduce the pharmacokinetic variations of docetaxel.
Drug-drug interactions related to CYPs also modulate the pharmacokinetic profiles of anticancer drugs.
These factors should be considered when trying to optimize and individualize chemotherapy.
Key Words: CYP, anticancer drugs, interindividual variation, individualized medicine, chemotherapy.

INTRODUCTION since cancer patients have heterogeneous backgrounds and

In general, differences in drug absorption, distribution,
metabolism and excretion result in interindividual variations
in the pharmacokinetics of a drug, if patients are adminis-
tered a uniform dose of the drug [1]. Among patients with
benign diseases treated with common drugs, relatively small
differences in drug pharmacokinetics including metabolism
are observed. Differences in outcomes are generally negligi-
ble because of the wide therapeutic windows of common
drugs. However, in cancer chemotherapy with anticancer
drugs, serious clinical consequences may occur from small
changes in drug metabolism and pharmacokinetics. Dosing
of anticancer drugs begins with Phase I studies which are
performed to determine a maximum-tolerated dose (MTD)1.
Subsequently, anticancer drugs are administered clinically to
patients at doses of MTD level or just below the MTD level.
The therapeutic windows are narrower compared to other
drugs used for common diseases. Therefore, pharmacoki-
netic variability is especially important in chemotherapy.
Accordingly, consideration of factors affecting pharmacoki-
netic profiles of anticancer drugs is needed. Recognition of
specific factors that might alter the response to chemothera-
peutic drugs in individual cancer patients can be difficult
*Address correspondence to this author at the Department of Clinical On-
cology, Saitama Medical School, 38 Morohongou, Moroyama-cho, Iruma-
gun, Saitama, 350-0495, Japan; Tel: +81-49-276-2134; Fax: +81-49-276-
2134; E-mail: fujitak@saitama-med.ac.jp
complex physiological changes that may be caused by con-
comitant disease status, organ dysfunction secondary to pre-
vious treatments, tumor invasions, malnutrition and poly-
pharmacy. Nevertheless, recent work has clearly revealed
that the pharmacokinetic properties of drugs, especially me-
tabolism, were important factors influencing the effective-
ness and the toxicity of anticancer drugs [2].
Drug metabolism is known to be catalyzed by a range of
drug-metabolizing enzymes including the cytochromes P450
(CYPs). CYPs are heme-containing enzymes that catalyze
the oxidation of a wide variety of endogenous and exogenous
compounds, including drugs, carcinogens, and other xenobi-
otics [3]. The CYP superfamily is composed of families, and
four of the families have the ability to catalyze the oxidation
of foreign chemicals, including a wide variety of anticancer
drugs. It is well known that CYP activities are affected by
several factors [1, 4, 5] including genetic polymorphisms;
changes in physiological conditions such as age and disease
states; intake of certain drugs or foods; or other environ-
mental factors such as smoking. Moreover, the large interin-
dividual differences in the constitutive expression of CYPs
in hepatocytes are sometimes observed. The variation of
CYP activities due to these factors may cause interindividual
variations in pharmacokinetic profiles of anticancer drugs
[2]. For example, genetic polymorphisms roughly segregate
patients into ‘poor metabolizer (PM)’ and ‘extensive me-
tabolizer (EM)’ phenotypes. In general, PM patients possess

1389-2002/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.

24 Current Drug Metabolism, 2006, Vol. 7, No. 1 Ken-ichi Fujita

reduced or absent ability to clear anticancer drugs compared
to EM patients, resulting in higher plasma concentrations of
the drugs and more toxic effects. The co-administration of
certain drugs or foods that modulate the activity of CYP en-
zymes may lead to decreased metabolic clearance of antican-
cer agents due to the inhibition of drug-metabolizing en-
zymes or to increased clearance due to enzyme induction.
The decrement of metabolic clearance of anticancer agents
may result in adverse drug reactions, while increased clear-
ance may cause insufficient tumor suppressive effects. Both
consequences can be severe.
Research related to the metabolism and pharmacokinetics
of cancer chemotherapeutic agents has been reviewed [1, 2,
4, 5], and it is increasingly apparent that the individualization
of the chemotherapy should take account of the factors that
modify the metabolism and pharmacokinetics of anticancer
agents.
In this review the roles of CYP enzymes in the metabo-
lism of anticancer drugs will be first described. Then, the
effects of the variability of CYP activities on the interindi-
vidual variations of pharmacokinetic profiles of anticancer
drugs will be discussed.
ROLES OF CYPS IN METABOLISM OF ANTI-
CANCER DRUGS
CYP enzymes are known to be involved in the metabo-
lism of a variety of anticancer drugs (Table 1). Specific iso-
forms responsible for the metabolism of each drug have been
identified through comprehensive in vitro experiments. Since
species differences in drug metabolism by CYPs have been
well documented, human CYP preparations should be used.
The metabolism of paclitaxel, for example, may be a case
demonstrating the remarkable species differences in CYP-
mediated metabolism between rats and humans [6, 7]. One of
major metabolites produced by human CYP2C8 (6α-
hydroxypaclitaxel) was not observed in rat bile. The in vitro
systems derived from human tissue developed to date in-
clude subcellular fractions (liver microsomes, cytosols and
homogenates), precision-cut liver slices, and hepatocytes [8-
18]. Besides these systems, genetically engineered cells ex-
pressing human CYPs have been established. Various host
cells are used for the heterologous expression of CYP iso-
forms. Among them, bacterial cells such as Escherichia coli
and Salmonella typhimurium have advantages with regard to
the ease of use and the high yield of protein [16-18].

Table 1. CYP Forms Responsible for the Metabolism of Anticancer Drugs

Form Anticancer drugs Pathway Reference*

CYP2A6 Tegafur 5'-Hydroxylation 74

CYP2B6 Cyclophosphamide 4-Hydroxylation 40,41

Ifosfamide 4-Hydroxylation 40,41

N-Dechloroethylation 43

CYP2C8 Paclitaxel 6α-Hydroxylation 6,7,62

CYP2C9 Cyclophosphamide 4-Hydroxylation 42

CYP2C19 Thalidomide 5- and 5'-Hydroxylations 73

CYP2D6 Tamoxifen 4-Hydroxylation 51-53

Endoxifen formation (Secondary metabolite) 51-53

CYP3A4/5 Cyclophosphamide 4-Hydroxylation 40,41

N-Dechloroethylation 43

Docetaxel Hydroxylation 63

Etoposide O-Demethylation 21-23

Gefitinib O-Demethylation 34,35

Ifosfamide 4-Hydroxylation 40,41

N-Dechloroethylation 43

Imatinib N-Demethylation Prescription information

Paclitaxel 3'-p-Hydroxylation 6,7,62

Tamoxifen N-Demethylation 51-53

Teniposide O-Demethylation 21

Vinca alkaloids Unidentified 75-77

* The numbers refer to the numbered references in the text.
Cytochrome P450 and Anticancer Drugs
Epipodophyllotoxins
Etoposide and teniposide are semisynthetic derivatives of
epipodophyllotoxin. These anticancer drugs are phase-
specific cytotoxic agents acting in the late S and early G2
phases of the cell cycle. They appear to act by causing
breaks in DNA via an interaction with DNA topoisomerase
II or by the formation of free radicals.
Etoposide is a clinically important antitumor agent de-
rived from 4’-demethylepipodophyllotoxin which is extracted
from Podophyllum peltatum or Podophyllum emodi [19, 20].
Etoposide is used during chemotherapy for a wide range of
malignancies (e.g. small cell lung cancer, acute leukemia,
lymphoma, testicular cancer) as a single agent or in combi-
nation with other agents [20]. The metabolism of etoposide
was investigated by using human liver microsomes and re-
combinant human CYP isoforms to identify the CYP forms
involved in the major metabolic pathway (O-demethylation)
of etoposide [21-23]. According to the experiments using the
recombinant CYP forms, the etoposide O-demethylation
was mediated mainly by CYP3A4 and to a minor extent
by CYP1A2, CYP2E1 and CYP3A5, whereas CYP2A6,
CYP2B6, CYP2C8 and CYP2C9 did not contribute to its
metabolism [21]. Another epipodophyllotoxin, teniposide, is
also mainly metabolized by CYP3A4 and to a lesser degree
by CYP3A5 [21]. CYP2A6, CYP2B6, CYP2C8 and CYP2C9
do not play roles in the O-demethylation of teniposide.
Molecular Targeted Anticancer Drugs
Recently, molecular targeted anticancer drugs have been
developed to target steps in signal transduction, angiogene-
sis, or the proteasome. The molecular targeted drugs can be
either small molecules or antibodies. CYPs are responsible
for the metabolism of small molecules but not antibodies.
Imatinib
Imatinib mesylate (Gleevec, ST1571) is a potent com-
petitive inhibitor of tyrosine kinases (TKs) associated with
BCR-ABL [24, 25], Kit [26, 27], which impedes the interac-
tion of ATP with the Src homology 1 domain of these pro-
teins, thereby inhibiting the phosphorylation of target pro-
teins acting downstream of the signal transduction. Imatinib
is a phenylaminopyrimidine derivative and represents the
first of a new class of drug known as signal transduction
inhibitors. Following initial Phase I and II dose-escalation
studies of imatinib [28-31], studies have demonstrated re-
markable efficacy with minimal side effects not only in
Philadelphia-positive leukemia (BCR-ABL positive) but also
in solid tumors such as gastrointestinal stromal tumors ex-
pressing Kit [32, 33]. CYP3A4 is the major CYP involved in
the microsomal biotransformation of imatinib (Prescription
information, Novartis Pharmaceuticals Corporation, East
Hanover).
Gefitinib
Gefitinib (Iressa; AZ1839) is a member of a new class of
oral drugs that inhibit receptor TKs, including the epidermal
growth factor receptor TK [34]. This anticancer drug re-
ceived approval as monotherapy for patients with locally
advanced or metastatic non-small cell lung cancer after fail-
Current Drug Metabolism, 2006, Vol. 7, No. 1 25
ure of both platinum-based and docetaxel chemotherapy.
Gefitinib is extensively metabolized in the liver, predomi-
nantly by CYP3A4 [34, 35]. The known metabolic pathways
include dealkylation, O-demethylation and oxidative de-
fluorination. A recent report has shown that CYP3A5 and
CYP2D6 are also involved in the metabolism of gefitinib
[35].
Oxazaphosphorines
Cyclophosphamide and ifosfamide are oxazaphosphorine
derivatives which require metabolic activation by CYP to
exert their pharmacological activity. There are two distinct
metabolic pathways of these drugs.
The cytotoxicity of the oxazaphosphorine derivatives is
produced by a 4-hydroxymetabolite, which enters cells and
spontaneously decomposes to phosphoramide mustard and
acrolein [36]. Phosphoramide mustard is a bifunctional al-
kylator of DNA and is the ultimate cytotoxic metabolite of
the oxazaphosphorine derivatives [37-39]. Liver microsomal
CYP2B6 and CYP3A preferentially catalyzed cyclophos-
phamide and ifosfamide 4-hydroxylation, respectively [40,
41]. On the other hand, Ren et al. [42] have demonstrated
that CYP2C9 and CYP3A seemed to be the major CYPs
responsible for the 4-hydroxycyclophosphamide formation at
low and high concentrations of the parent compound, re-
spectively.
Alternatively, the oxazaphosphorine derivatives can be
metabolized to a deschloroethylmetabolite, yielding the renal
and neurotoxic metabolite chloroacetaldehyde. The deschlo-
roethylmetabolite has no antitumor activity. The N-dechloro-
ethylation pathway of cyclophosphamide is catalyzed by
CYP3A4, but for ifosfamide it is catalyzed by both CYP3A4
and CYP2B6 [43].
Despite their structural similarities, cyclophosphamide
and ifosfamide exhibit marked differences in their metabo-
lism, toxicity, and therapeutic spectrum. Approximately 45%
of a therapeutic dose of ifosfamide is typically metabolized
via N-dechloroethylation, whereas only 10% of cyclophos-
phamide is converted via this pathway [44]. Consequently,
more patients developed deschloroethylmetabolite-induced
neurotoxicity and nephrotoxicity after ifosfamide treatment
than cyclophosphamide treatment. Clinically, neurotoxicity
and nephrotoxicity are dose-limiting factors for ifosfamide
treatment [45]. Neurotoxicity occurs in about 20% of pa-
tients after ifosfamide treatment, but is rare in cyclophos-
phamide treated patients. For these reasons, it is likely that
the safety and the therapeutic effects of oxazaphosphorine
derivatives could be improved by minimizing the N-
dechloroethylation pathway.
The oxazaphosphorine derivatives contain a chiral phos-
phorous atom. They are commonly used as racemic mixtures
of (+)-R and (-)-S enantiomers. According to an in vitro
study on the stereoselective metabolism of ifosfamide, the R-
enantiomer shows more favorable properties than the S-
enantiomer with respect to less extensive N-dechloro-
ethylation and more rapid 4-hydroxylation, indicating that R-
ifosfamide may have a distinct clinical advantage over race-
mic ifosfamide [46].
26 Current Drug Metabolism, 2006, Vol. 7, No. 1
Tamoxifen
The selective estrogen receptor modulator, tamoxifen,
has been widely used for more than 25 years for the endo-
crine treatment of all stages of hormone receptor–positive
breast cancer [47]. Tamoxifen is also approved by the United
States Food and Drug Administration for the prevention of
breast cancer in women at high risk for developing the dis-
ease [48].
Jordan et al. [49] demonstrated that hepatic metabolism
of tamoxifen resulted in a statistically significant increase in
its efficacy in vivo; they also showed for the first time that 4-
hydroxytamoxifen, one of the human tamoxifen metabolites,
was approximately 100 times more potent than tamoxifen as
an estrogen antagonist in vitro. The tamoxifen metabolite N-
desmethyltamoxifen is 100 times less active than tamoxifen
in vitro [50], although it is more abundant in plasma of pa-
tients receiving tamoxifen treatment than tamoxifen itself.
Recently, the activity of another tamoxifen metabolite, en-
doxifen (4-hydroxy-N-desmethyltamoxifen), which is pre-
sent at notably higher concentrations than 4-hydroxytamox-
ifen in the plasma of breast cancer patients receiving chronic
tamoxifen therapy was characterized [51]. In a series of in
vitro studies [51], endoxifen exhibited the same potency and
efficacy as 4-hydroxytamoxifen in suppressing estrogen-
dependent breast cancer cell growth and gene expression.
Tamoxifen is metabolized extensively by human liver
enzymes to primary and secondary metabolites [51-53]. A
comprehensive kinetic characterization of tamoxifen se-
quential metabolism in vitro demonstrated that CYP3A is the
major CYP subfamily responsible for the formation of N-
desmethyltamoxifen, whereas the generation of 4-hydroxy-
tamoxifen and endoxifen appeared to be predominantly
catalyzed by CYP2D6.
Although tamoxifen therapy is associated with benefits
for breast cancer, it is also associated with several adverse
events, including endometrial cancer [54]. Shibutani and
colleagues [55-58] demonstrated that a hydroxylated ta-
moxifen metabolite, α-hydroxytamoxifen, produced by hu-
man CYP3A was further metabolized by sulfotransferases to
form an O-sulfonated metabolite that produced tamoxifen-
DNA adducts. The tamoxifen-DNA adducts were detected in
the endometrium of women taking tamoxifen. These results
suggest the α-hydroxytamoxifen may be responsible for the
adverse carcinogenic effects of tamoxifen.
Taxanes
Taxanes are a family of structurally related compounds
that share a core ring structures referred to as baccatin III.
Two members of this family, paclitaxel and docetaxel, are
important anticancer drugs extensively used in the treatment
of various malignancies including ovarian cancer, breast
cancer and lung cancer [59].
The metabolism of paclitaxel has been studied in both
rats and human patients [6, 7]. The results showed that pa-
clitaxel metabolites observed in the bile of a human patients
were mostly different from those observed in rat bile [6, 7].
Nine metabolites were detectable in rat bile [60] and in five
metabolites were in the bile of a patient with metastatic cho-
langiocarcinoma [61]. Only one metabolite, 3’-p-hydroxy-
Ken-ichi Fujita
paclitaxel, was present in both human and rat bile. On the
other hand, one of the major metabolites present in human
bile, 6α-hydroxypaclitaxel, was not present in the rat bile
[61], indicating species differences in the biotransformation
of paclitaxel between rats and humans. The biotransforma-
tion of paclitaxel by human liver was investigated in vitro
with liver microsomes isolated from adults. Cresteil et al. [6]
first concluded that CYP2C accounted for the formation of
6α-hydroxypaclitaxel, which was the major metabolite
formed in vivo and in vitro, while CYP3A supported the 3’-
p-hydroxypaclitaxel formation. Subsequently, Rahman et al.
[62] demonstrated that 6α-hydroxypaclitaxel formation from
paclitaxel was catalyzed by CYP2C8.
In contrast to paclitaxel, the biotransformation pathway
of docetaxel is similar in animals and humans. The initial
metabolite resulted from the hydroxylation of the methyl of
the tert-butyl group at the C 13 side chain of docetaxel. Royer
et al. [63] have documented that docetaxel hydroxylation
was catalyzed by human CYP3A, based on the correlation of
the metabolism with CYP3A-dependent 6β-hydroxylation of
testosterone and 16-hydroxylation of dehydroepiandroster-
one, and inhibition with CYP3A inhibitors.
Thalidomide
Thalidomide is an old compound that was originally de-
veloped as a sedative. The drug was eventually withdrawn
from the general market because of its severe adverse effect
of teratogenesis. It has been reintroduced over the past sev-
eral years in the treatment of leprosy. More recently, the drug
has been found to be effective against various diseases in-
cluding multiple myeloma and prostate cancer, at least in
part, through the inhibition of angiogenesis [64-66]. Results
obtained so far suggested that thalidomide requires CYP
catalyzed biotransformation to exert its pharmacological
activities including antiangiogenesis [67-69], though the
exact mechanism of action has not been well clarified. Al-
though thalidomide is subject to spontaneous nonenzymatic
hydrolysis, these breakdown products may not be responsi-
ble for the pharmacological activity [70]. The hydroxylated
metabolites, 5-hydroxythalidomide, cis- and trans-5’hyd-
roxythalidomide, have been found in plasma or urine of pa-
tients [71, 72]. Recently, it has been reported that CYP2C19
is predominantly involved in the 5- and 5’-hydroxylation of
thalidomide in humans [73].
Tegafur
Tegafur is a prodrug of 5-fluorouracil (5-FU) synthesized
more than 30 years ago. The anticancer drug has been clini-
cally used for the treatment of mainly gastric and colon can-
cers because of the lower toxicity than 5-FU. 5-FU exerts its
cytotoxic effects via the inhibition of thymidylate synthase
and/or its incorporation into RNA molecules. The active
compound, 5-FU, is then further metabolized by dehydro-
pyrimidine dehydrogenase to form inactive metabolites. Te-
gafur is converted to 5-FU mainly in the liver through an
unstable intermediate, 5’-hydroxytegafur. The formation of
5-FU from tegafur is known to be mainly catalyzed by hu-
man CYP2A6 [74] as shown in experiments with human liver
microsomes that revealed a significant correlation between
5-FU formation from tegafur and 7-hydroxylation of cou-
marin, a representative metabolic reaction for CYP2A6.
Cytochrome P450 and Anticancer Drugs
Vinca Alkaloids
Vinca alkaloids, including vinblastine, vincristine, vinde-
sine and vinorelbine are anticancer drugs widely used in
combination with other drugs in cancer chemotherapy. They
have been known to exert their anticancer effects through the
inhibition of microtubule polymerization which causes the
antimitotic effect. These anticancer drugs were proven to be
metabolized by human CYP3A [75-77]. Vinorelbine bio-
transformation observed with human liver microsomes con-
sisted of one saturable and one nonsaturable processes with
Km and Vmax values of 1.90 µM and 25.3 pmol/min/mg
protein, respectively [77].
EFFECTS OF VARIABILITY OF CYPS ON INTER-
INDIVIDUAL VARIATIONS OF PHARMACOKINE-
TIC PROFILES OF ANTICANCER DRUGS
Cancer chemotherapy is characterized by a wide varia-
tion in response among patients. After the intake of identical
doses of a given agent, some patients may have clinically
significant adverse effects, whereas others may experience
no therapeutic response. The interpatient variability seen in
the response to anticancer drugs is, in part, caused by phar-
macokinetic factors. The most widely used traditional strat-
egy to decrease pharmacokinetic variability is to normalize a
drug dose to the patient’s body surface area (BSA). How-
ever, BSA-based dosing strategies often do not reduce inter-
individual variability in anticancer drug pharmacokinetics
[78], though BSA-based doses did, in fact, correlate with
paclitaxel area under the concentration-time curves (AUCs)
[79].
Some of the diversity in rates of response to anticancer
drugs can be ascribed to differences in the rate of drug me-
tabolism, particularly activity of CYP enzymes. Variability
among patients in the activity of these enzymes reflects a
complex interaction between both genetic and nongenetic
host factors and environmental factors. Therefore, the con-
sideration of these factors may be crucial to understanding
interpatient variability in response to anticancer drugs, and
ultimately to reducing it via personalized chemotherapy.
Genetic Variations of CYPs Related to Pharmacokinetics
of Anticancer Drugs
The results of a recent meta-analysis demonstrated that
adverse drug reactions were more likely for drugs metabo-
lized by enzymes that had genetic polymorphisms [80]. As
described above, CYP enzymes play essential roles in the
metabolism of various anticancer drugs. Therefore, the ef-
fects of genetic polymorphisms in CYP forms on the phar-
macokinetic properties of anticancer drugs are important to
consider.
CYP2A6
Several CYP2A6 alleles which alter CYP2A6 function
re caused by polymorphisms in the open reading frame of the
gene (see http://www.imm.ki.se/CYPalleles). Polymor-
phisms present in the 5’-flanking region of the CYP2A6 gene
which modify the transcriptional activity of CYP2A6 have
also been documented (http://www.imm.ki.se/CYPalleles).
Since CYP2A6 is responsible for the bioactivation of tegafur
Current Drug Metabolism, 2006, Vol. 7, No. 1 27
[74], CYP2A6 polymorphisms may affect the pharmacoki-
netics of tegafur. Patients with lower CYP2A6 activity may
benefit less from tegafur treatment because of insufficient
exposure to 5-FU.
In a clinical study, a newly developed anticancer drug S-
1, which contained tegafur and 5-chloro-2, 4-dihydroxypyri-
dine, an inhibitor of dihydropyrimidine dehydrogenase, was
orally administered to five gastric cancer patients. The total
AUC in one patient was four-fold higher than in other pa-
tients [81]. Alleles for the CYP2A6 genes derived from this
patient were completely sequenced [81]. CYP2A6*4A (iden-
tical to CYP2A6 *4C ) was found, which indicated the dele-
tion of an entire allele for the human CYP2A6 gene [82].
Another allele, CYP2A6*11 which is a novel mutant allele in
which thymine at nucleotide 670 is changed to cytosine was
also found. The nucleotide change caused an amino acid
change from serine at residue 224 to proline. The Vmax
value for tegafur metabolism by the mutant CYP2A6 was
approximately one-half of the value of the intact CYP2A6,
although the Km value was nearly the same. Therefore, the
higher AUC seen in the patient was attributed to the presence
of CYP2A6*4A and CYP2A6*11 alleles. The result supports
the hypothesis that patients possessing valiant alleles of the
CYP2A6 gene may not benefit from tegafur treatment. If
patients are homozygous for CYP2A6*4A genotype, the ac-
tivity of CYP2A6 may be absent, resulting in the null activa-
tion of tegafur. However, 5-FU is also known to be formed
from tegafur by liver cytosolic thymidine phosphorylase
[83]. The clinical significance of CYP2A6 activity on tegafur
biotransformation might also depend on the activity of the
cytosolic enzyme. Further clinical studies are needed to clar-
ify the role of CYP2A6 in the bioactivation of tegafur. The
CYP2A6 allele frequencies are shown in Table 2.
CYP2D6
The CYP2D6 gene is a polymorphic gene which has more
than 80 distinct allelic variants with 52 reported allelic vari-
ants (http://www.imm.ki.se/CYPalleles), many of which
result in the loss of CYP2D6 enzyme function [94]. Effects
of CYP2D6 polymorphism on the metabolism of anticancer
drugs have been increasingly studied.
The clinical effects of tamoxifen with respect to efficacy
and toxicity vary widely among individuals. For example,
among women with advanced breast cancer, roughly 35% of
those with estrogen receptor–positive tumors do not respond
to tamoxifen therapy, and all tumors that do respond eventu-
ally become resistant to tamoxifen treatment [45].
Jin et al. [95] investigated the mean plasma concentra-
tions of tamoxifen and its metabolites after 4 months of ta-
moxifen therapy in breast cancer patients with different
CYP2D6 genotype groups, based on the hypothesis that the
CYP2D6 genotype might affect the pharmacokinetics of ta-
moxifen and its metabolites. CYP2D6 genotype was not sta-
tistically significantly associated with mean plasma concen-
trations of tamoxifen, 4-hydroxytamoxifen and N-desmethyl-
tamoxifen. However, subjects who were CYP2D6*1/*3,
*1/*4, *1/*5, or *1/*6 heterozygotes (wild/variant genotype
group) had mean plasma endoxifen concentrations that were
55% of those of subjects who were homozygous for the wild
CYP2D6 genotype. Subjects who were CYP2D6*4/*4 homo-
28 Current Drug Metabolism, 2006, Vol. 7, No. 1 Ken-ichi Fujita

Table 2. CYP2A6 Allele Frequencies

Canadian
African-
Caucasian Japanese Korean Chinese Native
American
Indean

CYP2A6*1A 57.3 66.5 42.4 40.4 45.9 43.2

CYP2A6*1B 27.6 33.5 11.2 13 27.7 48.4 41.2 37.1 40.6 51.3 55

CYP2A6*1C 1.8

CYP2A6*1F 1.8 0

CYP2A6*1G 1.2 13.3

CYP2A6*1X2 0.7 0 0 0.4 0

CYP2A6*2 1.2 2 0 1.1 0 0 0 0 0 0

CYP2A6*4 1.2 1.9 20.1 24.2 11 15.1 6.7 1

(CYP2A6*4A) 3 0.5 18.4

(CYP2A6*4B) 0.24

(CYP2A6*4D) 0 0.5

CYP2A6*5 0.1 0 0 0 0.5 1 0.5 0.5

CYP2A6*6 0 0

CYP2A6*7 0.3 0 0 0 6.5 6.3 13 3.6 10 3.1 0

CYP2A6*8 0.1 0 2.2 1.6 1.4 3.6 0

CYP2A6*9 7.9 7.1 8 7.1 20.3 15.6 15.5

CYP2A6*10 0 0 1.1 1.6 0.5 0.4 0

*
CYP2A6*11

CYP2A6*12 2 0.4 0.8 0 0.5

CYP2A6*13 0 1.5

CYP2A6*14 3.6 0

CYP2A6*15 0 1.5

CYP2A6*17 0 9.4 0 0

CYP2A6*16 3.6 0

CYP2A6*18A 1.1 0 0 0.5

CYP2A6*18B 1.1 0 0 0

CYP2A6*19 0 0 0.5 1

CYP2A6*20 0 1.6 0 0
**
Reference 84 85 86 87 88 89 84 85 87 88 89 90 85 92 93 86 87 88 89 90 87 88 89 91 85 85
* Allele frequency of CYP2A6*11 has not yet been reported.
** The numbers refer to the numbered references in the text.
Details of the CYP2A6 gene polymorphisms are represented in http://www.imm.ki.se/CYPalleles/cyp2a6.htm.

zygotes (variant/variant genotype group) had mean plasma
endoxifen concentrations that were 26% of those of subjects
having the wild CYP2D6 genotype. Although, Jin et al. still
did not show direct evidence indicating the relationship be-
tween the efficacy of tamoxifen and CYP2D6 genotype,
these results may suggest that the clinical benefit of ta-
moxifen to breast cancer patients depends on the CYP2D6
genotype. The results of definitive clinical trials that include
outcomes such as breast cancer recurrence and mortality,
toxicity and secondary benefits are awaited. CYP2D6 allele
frequencies are shown in Table 3.
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 29

Table 3. CYP2D6 Allele Frequencies

Saudi
Caucasian European German Russian Spaniad Japanese Chinese Zimbabwean Ethiopian
Arabian

CYP2D6*1 36.4 32.2 70.8 42.3 43 40 26.9

CYP2D6*2 32.4 32.1 28.5 9.2 12.3 13 12.5 14.3

CYP2D6*3 2.04 1.6 1 0

CYP2D6*4 20.7 17.2 19.5 21.3 18.2 11.6 0.5 0.2 0 0.8 2 1.2 3.5

CYP2D6*5 6.9 4.1 2.1 2.4 3.9 6.1 4.5 6.2 5.7 5.7 4 3.3 1

CYP2D6*6 0.93 1.2 1.2

CYP2D6*8 0 0.1 0

CYP2D6*9 2.7

CYP2D6*10 1.53 2 1.6 4.2 40.8 38.1 38.6 50.7 5.6 8.6 3

(CYP2D6*10B) 1.3 50.7

CYP2D6*11 0 0.1

CYP2D6*12 0 0.1

CYP2D6*14 0 0.7 2.2 0

CYP2D6*15 0.08

CYP2D6*17 0.1 34 9 3

CYP2D6*18 0 0.2 0 0

CYP2D6*21 1 0

CYP2D6*36 37.1

CYP2D6*1X2 1.7 0.5

CYP2D6*2X2 1 1.8 0.5 3.5 0.5 0.9 2 16 10.4

*
Reference 96 97 98 99 100 99 101 102 98 98 103 99 104 99

* The numbers refer to the numbered references in the text.

Details of the CYP2D6 gene polymorphisms are represented in http://www.imm.ki.se/CYPalleles/cyp2d6.htm.

CYP3A4/CYP3A5 CYP3A4*17, and CYP3A4*18) have been shown to result

In adults, CYP3A4 and CYP3A5 are the most important
among the four CYP3A subfamily members for CYP3A-
mediated drug metabolism [105-107]. The genetic diversity
in the genes encoding these proteins has been reported [108].
Over 30 single nucleotide polymorphisms in CYP3A4
have been published, representing alleles CYP3A4*1 to
CYP3A4*19. However, most are very rare and unlikely to
impact CYP3A4 activity in vivo. The best characterized vari-
ant, a promoter variant with an adenine to guanine transition
at nucleotide –392 (CYP3A4*1B), was shown in vitro to ex-
hibit increased transcriptional activity [108-110]. Two re-
ports, however, indicate decreased transcriptional activity of
CYP3A4*1B [111, 112]. No association was observed be-
tween the CYP3A4*1B variant and CYP3A activity in studies
with healthy subjects using the CYP3A-phenotyping probes
midazolam [113-115], erythromycin [114, 116] and nifedip-
ine [117]. Three other CYP3A4 polymorphisms (CYP3A4*6,
in functional changes in CYP3A activity in vitro [118,
119]. The allele frequencies of CYP3A4 variants are show in
Table 4.
CYP3A5 is known to be expressed in only about 10% of
white subjects because of a splice variant in intron 3 of the
CYP3A5 gene at nucleotide position 6986 (CYP3A5*3) [127,
128]. Approximately 85 to 95% of white subjects, 70% of
Japanese, and 35 to 45% of blacks are homozygous for
CYP3A5*3 and thus deficient in CYP3A5 [127-129]. An-
other splice variant (CYP3A5*6), which is observed in black
populations, also results in the lack of CYP3A5 expression
[127, 128]. These results suggest that the metabolism of anti-
cancer drugs which depend mainly for their metabolism on
CYP3A5 may be polymorphic, although there is no antican-
cer drug which is specifically metabolized by CYP3A5
at present. The CYP3A5 allele frequencies are shown in
Table 5.
30 Current Drug Metabolism, 2006, Vol. 7, No. 1 Ken-ichi Fujita

Table 4. CYP3A4 Allele Frequencies

African- Japanese- Chinese- Hispanic- Middle Pacific

Caucasian African Asian Japanese Chinese Taiwanese Mexican
American American American American Eastern islander

CYP3A4*1

(CYP3A4*1A) 73.4

(CYP3A4*1B) 6.5 9 48 53 54.6 66.7 0 0 0 0 0 0 9.3 1 15 14

(CYP3A4*1G) 18.9

(CYP3A4*1H) 1

CYP3A4*2 0 2.7 0 0 0 0 0 0 0 0

CYP3A4*3 0 0.47 4.2 1.1 3.6 4.2 0 0 0 0 0 0 0 0

CYP3A4*4 0 0 0 0 1.47 0 0 0

CYP3A4*5 0 0 0 0 0.98 0 0 0

CYP3A4*6 0 0 0 0.1 0 0.49 0 0 0

CYP3A4*7 0 1.41 0 0 0 0 0 0

CYP3A4*8 0 0.33 0 0 0 0 0 0

CYP3A4*9 0 0.24 0 0 0 0 0 0

CYP3A4*10 2 0.24 2 0 0 5 0 0

CYP3A4*11 0 0.34 0 0 0.2 0 0 0 0

CYP3A4*12 0 0.34 0 0 0 0 0 0

CYP3A4*13 0 0.34 0 0 0 0 0 0

CYP3A4*14 0 0 0 0 0 0 0

CYP3A4*15 0 0 2 4.2 0 0 0 0 0 0

CYP3A4*16 0 0 5 1.4 0 5 0 0

CYP3A4*17 2.1 0 0

CYP3A4*18 0 0 2.1 2.8

CYP3A4*19 0 0 2.1

Reference* 120 121 118 122 123 124 125 120 125 123 124 118 118 120 126 123 120 119 124 123 125 123 120 120 120

* The numbers refer to the numbered references in the text.

Details of the CYP3A4 gene polymorphisms are represented in http://www.imm.ki.se/CYPalleles/cyp3a4.htm.

Phenotypic Variation of CYP3A4 Activity Related to
Pharmacokinetics of Anticancer Drugs
The enzyme activity of CYP3A4, which is responsible
for the biotransformation of a wide variety of anticancer
drugs (Table 1), exhibits a remarkable interindividual varia-
tion as high as 20 to 40 fold [108, 133]. In addition to the
large variation caused by the difference of constitutive ex-
pression, CYP3A4 expression is affected by the concomitant
intake of CYP3A4 inducers such as rifampicin. The co-
administration of therapeutic drugs which can modulate the
CYP3A4 activity can alter the metabolism of anticancer
drugs. It has been recently reported that liver function to-
gether with the concentration of the acute-phase reactant, α-1
acid glycoprotein, explained up to 18% of overall variation in
CYP3A activity [116].
Extensive attempts have been made to manipulate the
large variation of CYP3A4 activity and to reduce pharma-
cokinetic variability of the relevant drugs. Since the genetic
variations seen in CYP3A4 are estimated to be small as
mentioned above, phenotyping strategies to predict an indi-
vidual’s CYP3A activity before cytotoxic chemotherapy
treatment could be an appropriate approach for dose indi-
vidualization. Various noninvasive in vivo probes for evalu-
ating CYP3A activity have been described and several have
been shown to correlate with drug clearance [134-138]. The
most widely tested and accepted CYP3A probes are midazo-
lam, erythromycin and cortisol, although selection of the
ideal CYP3A-probe remains controversial [134-138].
Docetaxel, which is mainly metabolized by CYP3A4 in
humans [63], shows large interindividual variability in its
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 31

Table 5. CYP3A5 Allele Frequencies

Southwestern
African- Pacific
Caucasian African Asian Japanese Korean Chinese Mexican American
American Islander
Indian

CYP3A5*1 15 45 31 15 25 35 60

(CYP3A5*1B) 3 0.5

(CYP3A5*1C) 3 4.3

CYP3A5*2 5.26 1.9 0 0

CYP3A5*3 91.8 88 95.1 27 35 75 71 70 72 67

CYP3A5*4 0.9

CYP3A5*5 0.9

CYP3A5*6 0 13 17 0

CYP3A5*7 0 10 8 0

CYP3A5*8 0 4 0

CYP3A5*9 0 0 2

CYP3A5*10 2 0 0

CYP3A5*11*

Reference** 127 130 131 132 128 127 128 132 132 127 128 128 131 127 128 127 127 127

* The allele frequency of CYP3A5*11 has not yet been reported.

** The numbers refer to the numbered references in the text.
Details of the CYP3A5 gene polymorphisms are represented in http://www.imm.ki.se/CYPalleles/cyp3a5.htm.

pharmacokinetic/pharmacodynamic profiles [139, 140]. The
effects of inhibition and induction of CYP3A on docetaxel
pharmacokinetics was investigated in mice [141]. Pretreat-
ment of mice with the CYP3A inhibitor, ketoconazole, in-
creased the AUC of docetaxel, whereas treatment with the
CYP3A inducer, dexamethasone, decreased the AUC of do-
cetaxel. These findings suggest that enzymatic inhibition and
induction of CYP3A might affect docetaxel pharmacokinet-
ics and its antitumor potency in humans.
Attempts have been made to quantify the phenotypic
activity of CYP3A4 and to evaluate the correlation between
the activity and the pharmacokinetic parameters of do-
cetaxel. In a study with 21 sarcoma patients who were
treated with 100 mg/m2 of docetaxel, the erythromycin
breath test (ERMBT) using [ 14C-N-methyl]erythromycin was
employed to measure hepatic CYP3A activity in vivo [142].
The natural log of ERMBT accounted for 67% of the inter-
patient variability in the docetaxel clearance. In another
study, Yamamoto et al. [143] measured urinary 6β-
hydroxycortisol in 30 patients with non-small cell lung can-
cer treated with 60 mg/m2 docetaxel after the administration
of the 300 mg of hydroxycortisone. Cortisol is selectively
metabolized by CYP3A and excreted in the urine as 6β-
hydroxycortisol [138]. They used 300 mg of exogenous cor-
tisone, since the amount of 6β-hydroxycortisol produced
from endogenous cortisol was too low to be sensitively de-
tected in urine. Multivariate analysis revealed that the total
amount of 24 h urinary 6β-hydroxycortisol was the strongest
factor predicting docetaxel clearance. In a subsequent ran-
domized study, they examined whether individualized dosing
via CYP3A phenotyping could decrease the pharmacoki-
netic/pharmacodynamic variability of docetaxel compared to
more routine BSA-based dosing [144]. Fifty-nine patients
with advanced non-small cell lung cancer were randomly
assigned to either the BSA-based arm or the individualized
arm. In the BSA-based arm, 60 mg/m2 of docetaxel was ad-
ministered. In the individualized arm, the doses of docetaxel
were calculated from the estimated clearance and a target
AUC of 2.66 mg·h/L. The standard deviation of the AUC
was significantly smaller in the individualized arm than in
the BSA-based arm. The respective percentage decreases in
absolute neutrophil counts were 87.1±8.7% in the BSA-
based arm and 87.4±6.1% in the individualized arm. The
results indicate that the interpatient variability in percent
decreases in absolute neutrophil counts was slightly smaller
in the individualized arm. In another study, docetaxel clear-
ance was found to be correlated with midazolam clearance
[145].
These studies suggest that CYP3A4 activity could be a
useful indicator to predict in vivo docetaxel clearance and
toxicity, and that CYP3A4-guided dosing could be a useful
method for docetaxel dosing.
Irinotecan is a camptothecin analogue with potent antitu-
mor activity resulting from inhibition of topoisomerase I. It
is widely used for the treatment of colorectal and lung can-
cers [146-148]. Pharmacokinetic variability of irinotecan
among patients is also large. Pathways that eliminate irinote-
32 Current Drug Metabolism, 2006, Vol. 7, No. 1
can include CYP3A, carboxylesterase, UGT1A1, and drug-
transporting proteins [149]. CYP3A4 was reported to play a
role in irinotecan metabolism, though CYP3A5 did not
[150]. Mathijssen et al. [151] demonstrated a correlation
between irinotecan and midazolam clearance. Because dos-
ing strategies that were based on BSA did not reduce the
interindividual variability in irinotecan pharmacokinetics,
they recommended evaluating midazolam clearance com-
bined with the UGT1A1*28 polymorphism for optimizing
irinotecan chemotherapy. The active irinotecan metabolite,
SN-38, is further processed by glucuronidation. Their results
supported the idea that a CYP3A-guided strategy is applica-
ble for dosing anticancer drugs that are mainly metabolized
by CYP3A.
Drug Interactions Relevant to Anticancer Drugs
Metabolic drug-drug interactions occur when one drug
alters the activity of a drug-metabolizing enzyme, thereby
affecting the pharmacokinetics of drugs metabolized by the
enzyme. Various interactions have been reported thus far.
For example, the metabolism of terfenadine by human
CYP3A is known to be inhibited by azole antifungal drugs,
causing a notable increase in the plasma concentration of the
parent drug causing severe adverse drug reactions associated
with prolongation of the corrected QT interval in humans
[152]. The co-administration of drug(s) with anticancer
drugs has also been reported to induce drug interactions by
modifying their pharmacokinetic properties. Although, drug
interactions are generally considered to cause adverse drug
reactions, they sometimes might cause benefits such as an
improvement in drug bioavailability. For example, the inhi-
bition of CYPs in the small intestine may result in the eleva-
tion of the bioavailability of drugs which are orally adminis-
tered.
Docetaxel
A proof-of-concept study was carried out in 14 patients
with solid tumors [153]. In one course, patients received oral
docetaxel of 75 mg/m2 with or without a single oral dose of
cyclosporine A (15 mg/kg). During subsequent courses, pa-
tients received 100 mg/m2 of intravenous docetaxel. The
AUCs seen in patients who received oral docetaxel 75 mg/m2
with and without cyclosporine A were 2.71 ± 1.81 and 0.37 ±
0.33 mg·h/L, respectively. The absolute bioavailability of
oral docetaxel observed with or without cyclosporine A,
which was calculated from the mean AUC of intravenous
docetaxel, was 90 ± 44 or 8 ± 6%. Co-administration of oral
cyclosporine A strongly enhanced the oral bioavailability of
docetaxel. These data may form the basis for the further de-
velopment of a clinically useful oral formulation of do-
cetaxel.
Imatinib
Pharmacokinetic interactions of imatinib with substrates
and inhibitors of CYP3A4 have been studied. O’Brien et al.
[154] have evaluated the effect of the co-administration of
imatinib on the pharmacokinetics of simvastatin, a probe
CYP3A4 substrate. In total, 20 patients with chronic myeloid
leukemia received an oral dose of 40 mg simvastatin on
study day 1. On study days 2-7, each patient received 400
Ken-ichi Fujita
mg of imatinib once daily orally and on study day 8, 400 mg
imatinib together with 40 mg of simvastatin was given.
Imatinib increased the mean maximum concentration
(Cmax) value of simvastatin two-fold and the AUC value
3.5-fold compared with simvastatin alone. Recently, the ef-
fect of ketoconazole, a potent CYP3A inhibitor, on the
pharmacokinetics of imatinib was investigated [155]. Each
subject received a single oral dose of imatinib 200 mg alone,
and a single oral dose of imatinib 200 mg co-administered
with a single oral dose of ketoconazole 400 mg according to
a two-period crossover design. Following ketoconazole co-
administration, the mean imatinib Cmax and AUC increased
significantly by 26 and 40%, respectively. There was a sta-
tistically significant decrease in apparent clearance of
imatinib with a mean reduction of 28.6%. These interactions
should be considered when administering substrates or in-
hibitors of the CYP3A family in combination with imatinib.
Conversely, co-administration of rifampicin and St John’s
wort, which are potent inducers of CYP3A4, decreased the
Cmax and AUC of imatinib in healthy volunteers [156-158].
Therefore, the concomitant use of enzyme inducers may ne-
cessitate an increase in the imatinib dose to maintain clinical
effectiveness.
Paclitaxel
Glioma patients commonly receive anticonvulsants such
as phenytoin, phenobarbital and carbamazepine and corti-
costeroids that may increase the hepatic metabolism of pa-
clitaxel by CYPs. A Phase I study to determine the MTD of
paclitaxel administration as a 3 h infusion in patients with
recurrent malignant glioma was performed [159]. The MTD
for patients who received anticonvulsants was established to
be 360 mg/m2, whereas the MTD for patients who did not
receive anticonvulsants was 210 mg/m2. Pharmacokinetic
data demonstrated that the plasma paclitaxel levels and
clearance rates were similar for patients in both groups at
respective dose levels that produced dose-limiting toxicity.
These results indicate that the pharmacokinetics of paclitaxel
are altered by the co-administration of anticonvulsants, and
significantly larger doses of the drug can be administered to
patients with brain tumors who require anticonvulsants. Sub-
sequently, a Phase II study to confirm the effects of pacli-
taxel on recurrent malignant glioma was performed using
doses determined in the Phase I study. Unfortunately, no
objective clinical response to any dose of paclitaxel for re-
current malignant glioma was observed [160].
Tamoxifen
Jin et al. [95] demonstrated the effects of selective sero-
tonin reuptake inhibitors (SSRIs) that were also inhibitors of
CYP2D6 on the plasma level of endoxifen. SSRIs are com-
monly prescribed to treat hot flashes in breast cancer patients
who take tamoxifen. The concomitant administration of
SSRIs such as paroxetine substantially reduced the plasma
concentration of endoxifen, suggesting a potential alteration
in the expression of tamoxifen activity.
Vincristine
Although vinca alkaloids show similarity in their chemi-
cal structures, they exhibit marked differences in their re-
Cytochrome P450 and Anticancer Drugs
spective antitumor spectra, toxicity and pharmacokinetics
[161-163]. Moreover, their clinical pharmacokinetics shows
large intra- and/or inter-individual variations. Since these
agents are metabolized by CYP3A, it may be possible that
the variability of CYP3A activity is partly responsible for the
variation in the pharmacokinetic profiles of vinca alkaloids.
The effects of the CYP3A4-inducing antiepileptic agents,
carbamazepine and phenytoin, on the pharmacokinetics of
vincristine have been studied [164]. Fifteen adult patients
with brain tumors receiving combination chemotherapy with
procarbazine, lomustine, and vincristine volunteered for this
open parallel-group study. Nine of the patients used either
carbamazepine or phenytoin and six of the patients used no
obvious CYP3A4-inducing medication. The results revealed
that drugs inducing CYP3A4 could increase the elimination
of vincristine. Further studies are needed to determine
whether the increased clearance of vincristine by carba-
mazepine or phenytoin decreases the efficacy of vincristine.
Local Expression of CYPs in Tumor Tissues
Recently, a number of cancer tissues have been found to
express a variety of CYPs [165-172]. The local expression of
CYPs in tumor tissues appears to be important for tumor
management, since CYPs expressed in tumors may be re-
sponsible for the localized inactivation and/or activation of
anticancer drugs. Inactivation of anticancer drugs by CYPs
in tumor tissues may result in the resistance of the tumor
toward the drugs, while the activation of prodrugs by CYPs
may lead to the enhancement of effectiveness in cancer che-
motherapy. As shown in Table 1, CYP2A, CYP2B, CYP2C,
CYP2D and CYP3A are mainly responsible for the metabo-
lism of anticancer drugs. These forms of CYP have been
reported to be expressed in tumor tissues. CYP2A6 was
found to be expressed in breast cancer tissue obtained from a
Japanese patient (among 34 patients) [165]. CYP2B6 was
demonstrated to be present in breast tumor tissues [166,
167]. CYP2C enzymes were expressed in 33% of breast can-
cer tissues and 25% of prostate cancer tissues [168, 169].
The expression of CYP2D6 in breast tumors has been re-
ported by Iscan et al. [167]. CYP3A was found in 22% of
breast cancer by immunohistochemistry [170], however, the
enzyme was not detected in 34 specimens from Japanese
patients [165]. Murray et al. [171] have shown that CYP3A
was expressed in at least 60% of oesophageal carcinomas.
CYP3A has been also reported to be expressed in colon car-
cinomas and prostate cancer [169, 172].
It seems likely that there is a large interindividual vari-
ability in CYP expression in tumor tissues. This may also
contribute to the interindividual variability in the response to
chemotherapy. Indeed, Miyoshi et al. [173] demonstrated
that intratumoral expression of CYP3A4 mRNA was signifi-
cantly lower (about 4 fold) in responders compared with
nonresponders in docetaxel treatment. Further studies are
needed to clarify the roles of CYPs expressed in tumor tis-
sues in cancer chemotherapy.
One therapeutically attractive strategy to enhance the
intratumoral activation of a prodrug is based on the direct
transfer to the tumor of a gene which encodes an enzyme that
can activate the prodrug, and this gene therapy strategy has
Current Drug Metabolism, 2006, Vol. 7, No. 1 33
been developed in animal models. A CYP2B6 gene coding
for the enzyme that is responsible for the activation of cyclo-
phosphamide has been transferred into tumor cells with a
retrovirus and replication-conditional adenovirus to enhance
the intratumoral activation of prodrugs [174, 175].
PERSPECTIVES
Generally, for select drugs whose pharmacokinetic/phar-
macodynamic relationships are known, feedback control of
plasma concentrations, through therapeutic drug monitoring
(TDM), may be invoked to minimize the variability in their
therapeutic and toxic effects. However, for cancer che-
motherapeutic agents, TDM cannot be readily used to reduce
pharmacokinetic/pharmacodynamic variations because of the
following reasons:
§ The pharmacokinetic/pharmacodynamic relationships are
not well known;
§ The threshold of the antitumor effects is usually obscure
and dependent on the patient factors, which may not be
well quantified;
§ There is a long time lag between the treatment of patients
with anticancer drugs and the appearance of the efficacy
of the drugs (a large time constant);
§ It is difficult to determine the target drug to be monitored
because most cancer chemotherapeutics is based on in-
tentional polypharmacy; of the combination use of anti-
cancer drugs;
§ Dose adjustments may be difficult to make in chemother-
apy once dose-limiting toxicity thresholds have been
reached.
Therefore, the optimal dose of anticancer drugs should,
when possible, be established prior to drug administration.
Since CYP forms are responsible for the metabolism of a
wide variety of anticancer drugs and these enzymes show a
vast range of variability in their activities due to genetic and
nongenetic factors, CYP activity should be a good biomarker
for establishing individualized doses of anticancer drugs.
This is a feedforward concept for the determination of indi-
vidualized doses of anticancer drugs. Tests of this new con-
cept for initializing/optimizing chemotherapy are now in
progress.
ABBREVIATIONS
AUC = Area under the concentration-time curve
BSA = Body surface area
Cmax = Maximum concentration
CYP = Cytochrome P450
ERMBT = Erythromycin breath test
5-FU = 5-Fluorouracil
MTD = Maximum-tolerated dose
SSRI = Selective serotonin reuptake inhibitor
TK = Tyrosine kinase
34 Current Drug Metabolism, 2006, Vol. 7, No. 1
REFERENCES
[1] Wilkinson, G.R. (2005) N. Engl. J. Med., 352(21), 2211-2221.
[2] Rochat, B. (2005) Clin. Pharmacokinet., 44(4), 349-366.
[3] Nelson, D.R.; Koymans, L.; Kamataki, T.; Stegeman, J.J.; Feyere-
isen, R.; Waxman, D.J.; Waterman, M.R.; Gotoh, O.; Coon, M.J.;
Estabrook, R.W.; Gunsalus, I.C. and Nebert, D.W. (1996) Pharma-
cogenetics, 6(1), 1-42.
[4] Evans, W.E. and Relling, M.V. (2004) Nature, 429(6990), 464-
468.
[5] Evans, W.E. and McLeod, H.L. (2003) N. Engl. J. Med., 348(6),
538-549.
[6] Cresteil, T.; Monsarrat, B.; Alvinerie, P.; Treluyer, J.M.; Vieira, I.
and Wright, M. (1994) Cancer Res., 54(2), 386-392.
[7] Monsarrat, B.; Mariel, E.; Cros, S.; Gares, M.; Guenard, D.; Gue-
ritte-Voegelein, F. and Wright, M. (1990) Drug Metab. Dispos.,
18(6), 895-901.
[8] Eddershaw, P.J. and Dickins, M. (1999) Pharm. Sci. Technol. To-
day, 2(1), 13-19.
[9] Ekins, S.; Ring, B.J.; Grace, J.; McRobie-Belle, D.J. and Wrighton,
S.A. (2000) J. Pharmacol. Toxicol. Methods, 44(1), 313-324.
[10] LeCluyse, E.L. (2001) Eur. J. Pharm. Sci., 13(4), 343-368.
[11] Li, A.P.; Gorycki, P.D.; Hengstler, J.G.; Kedderis, G.L.; Koebe,
H.G.; Rahmani, R.; de Sousas, G.; Silva, J.M. and Skett, P. (1999)
Chem. Biol. Interact., 121(1), 117-123.
[12] Rodrigues, A.D. (1994) Biochem. Pharmacol., 48(12), 2147-2156.
[13] Streetman, D.S.; Bertino, J.S. and Nafziger, A.N. (2000) Pharma-
cogenetics, 10(3), 187-216.
[14] Venkatakrishnan, K.; von Moltke, L.L.; Obach, R.S. and Green-
blatt, D.J. (2003) Curr. Drug Metab., 4(5), 423-459.
[15] Venkatakrishnan, K.; von Moltke, L.L. and Greenblatt, D.J. (2001)
J. Clin. Pharmacol., 41(11), 1149-1179.
[16] Iwata, H.; Fujita, K.; Kushida, H.; Suzuki, A.; Konno, Y.; Naka-
mura, K.; Fujino, A. and Kamataki, T. (1998) Biochem. Pharma-
col., 55(8), 1315-1325.
[17] Fujita, K.; Nakayama, K.; Yamazaki, Y.; Tsuruma, K.; Yamada,
M.; Nohmi, T. and Kamataki, T. (2001) Environ. Mol. Mutagen.,
38(4), 329-338.
[18] Fujita, K. and Kamataki, T. (2002) Drug Metab. Pharmacokin.,
17(1), 1-22.
[19] Stahelin, H.F. and von Wartburg, A. (1991) Cancer Res., 51(1), 5-
15.
[20] Clark, P.I. and Slevin, M.L. (1987) Clin. Pharmacokinet., 12(4),
223-252.
[21] Relling, M.V.; Nemec, J.; Schuetz, E.G.; Schuetz, J.D.; Gonzalez,
F.J. and Korzekwa, K.R. (1994) Mol. Pharmacol., 45(2), 352-358.
[22] Kawashiro, T.; Yamashita, K.; Zhao, X.J.; Koyama, E.; Tani, M.;
Chiba, K. and Ishizaki, T. (1998) J. Pharmacol. Exp. Ther., 286(3),
1294-1300.
[23] Zhao, X.J.; Kawashiro, T. and Ishizaki, T. (1998) Drug Metab.
Dispos., 26(2), 188-191.
[24] Buchdunger, E.; Zimmermann, J.; Mett, H.; Meyer, T.; Muller, M.;
Druker, B.J. and Lydon, N.B. (1996) Cancer Res., 56(1), 100-104.
[25] Druker, B.J.; Tamura, S.; Buchdunger, E.; Ohno, S.; Segal, G.M.;
Fanning, S.; Zimmermann, J. and Lydon N.B. (1996) Nat. Med.,
2(5), 561-566.
[26] Buchdunger, E.; Cioffi, C.L.; Law, N.; Stover, D.; Ohno-Jones, S.;
Druker, B.J. and Lydon, N.B. (2000) J. Pharmacol. Exp. Ther.,
295(1), 139-145.
[27] Heinrich, M.C.; Griffith, D.J.; Druker, B.J.; Wait, C.L.; Ott, K.A.
and Zigler, A.J. (2000) Blood, 96(3), 925-932.
[28] Druker, B.J.; Sawyers, C.L.; Kantarjian, H.; Resta, D.J.; Reese,
S.F.; Ford, J.M.; Capdeville, R. and Talpaz, M. (2001) N. Engl. J.
Med., 344(14), 1038-1042.
[29] Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.;
Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, R.; Ohno-
Jones, S. and Sawyers, C.L. (2001) N. Engl. J. Med., 344(14),
1031-1037.
[30] Talpaz, M.; Silver, R.T.; Druker, B.J.; Goldman, J.M.; Gambacorti-
Passerini, C.; Guilhot, F.; Schiffer, C.A.; Fischer, T.; Deininger,
M.W.; Lennard, A.L.; Hochhaus, A.; Ottmann, O.G.; Gratwohl, A.;
Baccarani, M.; Stone, R.; Tura, S.; Mahon, F.X.; Fernandes-Reese,
S.; Gathmann, I.; Capdeville, R.; Kantarjian, H.M. and Sawyers,
C.L. (2002) Blood, 99(6), 1928-1937.
[31] Kantarjian, H.; Sawyers, C.; Hochhaus, A.; Guilhot, F.; Schiffer,
C.; Gambacorti-Passerini, C.; Niederwieser, D.; Resta, D.; Cap-
Ken-ichi Fujita
deville, R.; Zoellner, U.; Talpaz, M.; Druker, B.; Goldman, J.;
O'Brien, S.G.; Russell, N.; Fischer, T.; Ottmann, O.; Cony-
Makhoul, P.; Facon, T.; Stone, R.; Miller, C.; Tallman, M.; Brown,
R.; Schuster, M.; Loughran, T.; Gratwohl, A.; Mandelli, F.; Saglio,
G.; Lazzarino, M.; Russo, D.; Baccarani, M.; Morram, E. and In-
ternational STI571 CML Study Group. (2002) N. Engl. J. Med.,
346(9), 645-652.
[32] O'Brien, S.G.; Guilhot, F.; Larson, R.A.; Gathmann, I.; Baccarani,
M.; Cervantes, F.; Cornelissen, J.J.; Fischer, T.; Hochhaus, A.;
Hughes, T.; Lechner, K.; Nielsen, J.L.; Rousselot, P.; Reiffers, J.;
Saglio, G.; Shepherd, J.; Simonsson, B.; Gratwohl, A.; Goldman,
J.M.; Kantarjian, H.; Taylor, K.; Verhoef, G.; Bolton, A.E.;
Capdeville, R.; Druker, B.J. and IRIS Investigators. (2003) N. Engl.
J. Med., 348(11), 994-1004.
[33] Joensuu, H.; Roberts, P.J.; Sarlomo-Rikala, M.; Andersson, L.C.;
Tervahartiala, P.; Tuveson, D.; Silberman, S.; Capdeville, R.;
Dimitrijevic, S.; Druker, B. and Demetri, G.D. (2001) N. Engl. J.
Med., 344(14), 1052-1056.
[34] Cohen, M.H.; Williams, G.A.; Sridhara, R.; Chen, G.; McGuinn,
W.D. Jr; Morse, D.; Abraham, S.; Rahman, A.; Liang, C.; Lostritto,
R.; Baird, A. and Pazdur, R. (2004) Clin. Cancer Res., 10(4), 1212-
1218.
[35] McKillop, D.; McCormick, A.D.; Millar, A.; Miles, G.S.; Phillips,
P.J. and Hutchison, M. (2005) Xenobiotica, 35(1), 39-50.
[36] Sladek, N.E. (1994) In Anticancer Drugs: Reactive Metabolism
and Drug Interactions (Powis, G. ed.), Pergamon Press, New York,
pp. 79-156.
[37] Colvin, M.; Padgett, C.A. and Fenselau, C. (1973) Cancer Res.,
33(4), 915-918.
[38] Connors, T.A.; Cox, P.J.; Farmer, P.B.; Foster, A.B. and Jarman,
M. (1974) Biochem. Pharmacol., 23(1), 115-129.
[39] Struck, R.F.; Kirk, M.C.; Witt, M.H. and Laster, W.R. Jr. (1975)
Biomed. Mass. Spectrom., 2(1), 46-52.
[40] Walker, D.; Flinois, J.P.; Monkman, S.C.; Beloc, C.; Boddy, A.V.;
Cholerton, S.; Daly, A.K.; Lind, M.J.; Pearson, A.D. and Beaune,
P.H. (1994) Biochem. Pharmacol., 47(7), 1157-1163.
[41] Chang, T.K.; Weber, G.F.; Crespi, C.L. and Waxman, D.J. (1993)
Cancer Res., 53(23), 5629-5637.
[42] Ren, S.; Yang, J.S.; Kalhorn, T.F. and Slattery, J.T. (1997) Cancer
Res., 57(19), 4229-4235.
[43] Huang, Z.; Roy, P. and Waxman, D.J. (2000) Biochem. Pharma-
col., 59(8), 961-972.
[44] Kaijser, G.P.; Korst, A.; Beijnen, J.H.; Bult, A. and Underberg,
W.J. (1993) Anticancer Res., 13(5A), 1311-1324.
[45] Fleming, R.A. (1997) Pharmacotherapy, 17(5 Pt 2), 146S-154S.
[46] Roy, P.; Tretyakov, O.; Wright, J. and Waxman, D.J. (1999) Drug
Metab. Dispos., 27(11), 1309-1318.
[47] Osborne, C.K. (1998) N. Engl. J. Med., 339(22), 1609-1618.
[48] Fisher, B.; Costantino, J.P.; Wickerham, D.L.; Redmond, C.K.;
Kavanah, M.; Cronin, W.M.; Vogel, V.; Robidoux, A.; Dimitrov,
N.; Atkins, J.; Daly, M.; Wieand, S.; Tan-Chiu, E.; Ford, L. and
Wolmark, N. (1998) J. Natl. Cancer Inst., 90(18), 1371-1388.
[49] Jordan, V.C.; Collins, M.M.; Rowsby, L. and Prestwich, G. (1977)
J. Endocrinol., 75(2), 305-316.
[50] Fabian, C.; Tilzer, L. and Sternson, L. (1981) Biopharm. Drug.
Dispos., 2(4), 381-390.
[51] Stearns, V.; Johnson, M.D.; Rae, J.M.; Morocho, A.; Novielli, A.;
Bhargava, P.; Hayes, D.F.; Desta, Z. and Flockhart, D.A. (2003) J.
Natl. Cancer Inst., 95(23), 1758-1764.
[52] Crewe, H.K.; Ellis, S.W.; Lennard, M.S. and Tucker, G.T. (1997)
Biochem. Pharmacol., 53(2), 171-178.
[53] Desta, Z.; Ward, B.A.; Soukhova, N.V. and Flockhart, D.A. (2004)
J. Pharmacol. Exp. Ther., 310(3), 1062-1075.
[54] Swerdlow, A.J.; Jones, M.E. and British Tamoxifen Second Cancer
Study Group. (2005) J. Natl. Cancer Inst., 97(5), 375-384.
[55] Shibutani, S.; Dasaradhi, L.; Terashima, I.; Banoglu, E. and Duffel,
M.W. (1998) Cancer Res., 58(4), 647-653.
[56] Shibutani, S.; Ravindernath, A.; Suzuki, N.; Terashima, I.;
Sugarman, S.M.; Grollman, A.P. and Pearl, M.L. (2000) Carcino-
genesis, 21(8), 1461-1467.
[57] Kim, S.Y.; Suzuki, N.; Santosh, Laxmi, Y.R.; Rieger, R. and Shi-
butani, S. (2003) Chem. Res. Toxicol., 16(9), 1138-1144.
[58] Kim, S.Y.; Suzuki, N.; Laxmi, Y.R.; McGarrigle, B.P.; Olson, J.R.;
Sharma, M.; Sharma, M. and Shibutani, S. (2005) Chem. Res. Toxi-
col., 18(5), 889-895.
[59] Rowinsky, E.K. (1997) Annu. Rev. Med., 48, 353-374.
Cytochrome P450 and Anticancer Drugs
[60] Monsarrat, B.; Alvinerie, P.; Wright, M.; Dubois, J.; Gueritte-
Voegelein, F.; Guenard, D.; Donehower, R.C. and Rowinsky, E.K.
(1993) J. Natl. Cancer Inst. Monogr., 15, 39-46.
[61] Monsarrat, B.; Wright, M.; Dubois, J.; Gueritte-Voegelein, F.;
Guenard, D.; Rowinsky, E.K. and Donehower, R.C. (1992) Ann.
Oncol., 3(Suppl. 1), 123.
[62] Rahman, A.; Korzekwa, K.R.; Grogan, J.; Gonzalez, F.J. and Har-
ris, J.W. (1994) Cancer Res., 54(21), 5543-5546.
[63] Royer, I.; Monsarrat, B.; Sonnier, M.; Wright, M. and Cresteil, T.
(1996) Cancer Res., 56(1), 58-65.
[64] Richardson, P.; Hideshima, T. and Anderson, K. (2002) Annu. Rev.
Med., 53, 629-657.
[65] D'Amato, R.J.; Loughnan, M.S.; Flynn, E. and Folkman, J. (1994)
Proc. Natl. Acad. Sci. USA, 91(9), 4082-4085.
[66] Figg, W.D.; Dahut, W.; Duray, P.; Hamilton, M.; Tompkins, A.;
Steinberg, S.M.; Jones, E.; Premkumar, A.; Linehan, W.M.;
Floeter, M.K.; Chen, C.C.; Dixon, S.; Kohler, D.R.; Kruger, E.A.;
Gubish, E.; Pluda, J.M. and Reed, E. (2001) Clin. Cancer Res.,
7(7), 1888-1893.
[67] Singhal, S.; Mehta, J.; Desikan, R.; Ayers, D.; Roberson, P.; Ed-
dlemon, P.; Munshi, N.; Anaissie, E.; Wilson, C.; Dhodapkar, M.;
Zeddis, J. and Barlogie, B. (1999) N. Engl. J. Med., 341(21), 1565-
1571.
[68] Braun, A.G.; Harding, F.A. and Weinreb, S.L. (1986) Toxicol.
Appl. Pharmacol., 82(1), 175-179.
[69] Bauer, K.S.; Dixon, S.C. and Figg, W.D. (1998) Biochem.
Pharmacol., 55(11), 1827-1834.
[70] Braun, A.G. and Weinreb, S.L. (1985) Teratog. Carcinog.
Mutagen., 5(3), 149-158.
[71] Eriksson, T.; Bjorkman, S.; Roth, B.; Bjork, H. and Hoglund, P.
(1998) J. Pharm. Pharmacol., 50(12), 1409-1416.
[72] Teo, S.K.; Sabourin, P.J.; O'Brien, K.; Kook, K.A. and Thomas,
S.D. (2000) J. Biochem. Mol. Toxicol., 14(3), 140-147.
[73] Ando, Y.; Fuse, E. and Figg, W.D. (2002) Clin. Cancer Res., 8(6),
1964-1973.
[74] Ikeda, K.; Yoshisue, K.; Matsushima, E.; Nagayama, S.; Kobaya-
shi, K.; Tyson, C.A.; Chiba, K. and Kawaguchi, Y. (2000) Clin.
Cancer Res., 6(11), 4409-4415.
[75] Zhou-Pan, X.R.; Seree, E.; Zhou, X.J.; Placidi, M.; Maurel, P.;
Barra, Y. and Rahmani, R. (1993) Cancer Res., 53(21), 5121-5126.
[76] Zhou, X.J.; Zhou-Pan, X.R.; Gauthier, T.; Placidi, M.; Maurel, P.
and Rahmani, R. (1993) Biochem. Pharmacol., 45(4), 853-861.
[77] Kajita, J.; Kuwabara, T.; Kobayashi, H. and Kobayashi, S. (2000)
Drug Metab. Dispos., 28(9), 1121-1127.
[78] Baker, S.D.; Verweij, J.; Rowinsky, E.K.; Donehower, R.C.;
Schellens, J.H.; Grochow, L.B. and Sparreboom, A. (2002) J. Natl.
Cancer Inst., 94(24), 1883-1888.
[79] Ando, Y.; Ohtsu, T.; Ando, M.; Ohyanagi, F.; Nagashima, F.; Na-
rabayashi, M.; Saijo, N. and Sasaki, Y. (2003) J. Natl. Cancer Inst.,
95(21), 1638-1640.
[80] Phillips, K.A.; Veenstra, D.L.; Oren, E.; Lee, J.K. and Sadee, W.
(2001) JAMA, 286(18), 2270-2279.
[81] Daigo, S.; Takahashi, Y.; Fujieda, M.; Ariyoshi, N.; Yamazaki, H.;
Koizumi, W.; Tanabe, S.; Saigenji, K.; Nagayama, S.; Ikeda, K.;
Nishioka, Y. and Kamataki T. (2002) Pharmacogenetics, 12(4),
299-306.
[82] Nunoya, K.; Yokoi, T.; Kimura, K.; Inoue, K.; Kodama, T.; Fu-
nayama, M.; Nagashima, K.; Funae, Y.; Green, C.; Kinoshita, M.
and Kamataki, T. (1998) Pharmacogenetics, 8(3), 239-249.
[83] Komatsu, T.; Yamazaki, H.; Shimada, N.; Nagayama, S.; Kawa-
guchi, Y.; Nakajima, M. and Yokoi, T. (2001) Clin. Cancer Res.,
7(3), 675-681.
[84] Nakajima, M.; Yoshida, R.; Fukami, T.; McLeod, H.L. and Yokoi,
T. (2004) FEBS Lett., 569(1-3), 75-81.
[85] Schoedel, K.A.; Hoffmann, E.B.; Rao, Y.; Sellers, E.M. and
Tyndale, R.F. (2004) Pharmacogenetics, 14(9), 615-626.
[86] Kiyotani, K.; Fujieda, M.; Yamazaki, H.; Shimada, T.; Guengerich,
F.P.; Parkinson, A.; Nakagawa, K.; Ishizaki, T. and Kamataki, T.
(2002) Drug Metab. Pharmacokinet., 17(5), 482-487.
[87] Fukami, T.; Nakajima, M.; Higashi, E.; Yamanaka, H.; Sakai, H.;
McLeod, H.L. and Yokoi, T. (2005) Drug Metab. Dispos., 33(8),
1202-1210.
[88] Fukami, T.; Nakajima, M.; Yoshida, R.; Tsuchiya, Y.; Fujiki, Y.;
Katoh, M.; McLeod, H.L. and Yokoi, T. (2004) Clin. Pharmacol.
Ther., 76(6), 519-527.
Current Drug Metabolism, 2006, Vol. 7, No. 1 35
[89] Fukami, T.; Nakajima, M.; Higashi, E.; Yamanaka, H.; McLeod,
H.L. and Yokoi, T. (2005) Biochem. Pharmacol., 70(5), 801-808.
[90] Yoshida, R.; Nakajima, M.; Watanabe, Y.; Kwon, J.T. and Yokoi,
T. (2002) Br. J. Clin. Pharmacol., 54(5), 511-517.
[91] Oscarson, M.; McLellan, R.A.; Gullsten, H.; Agundez, J.A.;
Benitez, J.; Rautio, A.; Raunio, H.; Pelkonen, O. and Ingelman-
Sundberg, M. (1999) FEBS Lett., 460(2), 321-327.
[92] Ariyoshi, N.; Takahashi, Y.; Miyamoto, M.; Umetsu, Y.; Daigo, S.;
Tateishi, T.; Kobayashi, S.; Mizorogi, Y.; Loriot, M.A.; Stucker, I.;
Beaune, P.; Kinoshita, M. and Kamataki, T. (2000) Pharmacoge-
netics, 10(8), 687-693.
[93] Ariyoshi, N.; Sekine, H.; Nakayama, K.; Saito, K.; Miyamoto, A.
and Kamataki, T. (2004) Pharmacogenetics, 14(10), 701-705.
[94] Caraco, Y. (2004) N. Engl. J. Med., 351(27), 2867-2869.
[95] Jin, Y.; Desta, Z.; Stearns, V.; Ward, B.; Ho, H.; Lee, K.H.; Skaar,
T.; Storniolo, A.M.; Li, L.; Araba, A.; Blanchard, R.; Nguyen, A.;
Ullmer, L.; Hayden, J.; Lemler, S.; Weinshilboum, R.M.; Rae,
J.M.; Hayes, D.F. and Flockhart, D.A. (2005) J. Natl. Cancer Inst. ,
97(1), 30-39.
[96] Sachse, C.; Brockmoller, J.; Bauer, S. and Roots, I. (1997) Am. J.
Hum. Genet., 60(2), 284-295.
[97] Marez, D.; Legrand, M.; Sabbagh, N.; Guidice, J.M.; Spire, C.;
Lafitte, J.J.; Meyer, U.A. and Broly, F. (1997) Pharmacogenetics,
7(3), 193-202.
[98] Kubota, T.; Yamaura, Y.; Ohkawa, N.; Hara, H. and Chiba, K.
(2000) Br. J. Clin. Pharmacol., 50(1), 31-34.
[99] McLellan, R.A.; Oscarson, M.; Seidegard, J.; Evans, D.A. and
Ingelman-Sundberg, M. (1997) Pharmacogenetics, 7(3), 187-191.
[100] Gaikovitch, E.A.; Cascorbi, I.; Mrozikiewicz, P.M.; Brockmoller,
J.; Frotschl, R.; Kopke, K.; Gerloff, T.; Chernov, J.N. and Roots, I.
(2003) Eur. J. Clin. Pharmacol., 59(4), 303-312.
[101] Tateishi, T.; Chida, M.; Ariyoshi, N.; Mizorogi, Y.; Kamataki, T.
and Kobayashi, S. (1999) Clin. Pharmacol. Ther., 65(5), 570-575.
[102] Nishida, Y.; Fukuda, T.; Yamamoto, I. and Azuma, J. (2000)
Pharmacogenetics, 10(6), 567-570.
[103] Johansson, I.; Oscarson, M.; Yue, Q.Y.; Bertilsson, L.; Sjoqvist, F.
and Ingelman-Sundberg, M. (1994) Mol. Pharmacol., 46(3), 452-
459.
[104] Aklillu, E.; Persson, I.; Bertilsson, L.; Johansson, I.; Rodrigues, F.
and Ingelman-Sundberg, M. (1996) J. Pharmacol. Exp. Ther.,
278(1), 441-446.
[105] de Wildt, S.N.; Kearns, G.L.; Leeder, J.S. and van den Anker, J.N.
(1999) Clin. Pharmacokinet., 37(6), 485-505.
[106] Koch, I.; Weil, R.; Wolbold, R.; Brockmoller, J.; Hustert, E.; Burk,
O.; Nuessler, A.; Neuhaus, P.; Eichelbaum, M.; Zanger, U. and
Wojnowski, L. (2002) Drug Metab. Dispos., 30(10), 1108-1114.
[107] Williams, J.A.; Ring, B.J.; Cantrell, V.E.; Jones, D.R.; Eckstein, J.;
Ruterbories, K.; Hamman, M.A.; Hall, S.D. and Wrighton, S.A.
(2002) Drug Metab. Dispos., 30(8), 883-891.
[108] Lamba, J.K.; Lin, Y.S.; Schuetz, E.G. and Thummel, K.E. (2002)
Adv. Drug Deliv. Rev., 54(10), 1271-1294.
[109] Amirimani, B.; Walker, A.H.; Weber, B.L. and Rebbeck, T.R.
(1999) J. Natl. Cancer Inst., 91(18), 1588-1590.
[110] Ando, Y.; Tateishi, T.; Sekido, Y.; Yamamoto, T.; Satoh, T.; Hase-
gawa, Y.; Kobayashi, S.; Katsumata, Y.; Shimokata, K. and Saito,
H. (1999) J. Natl. Cancer Inst., 91(18), 1587-1590.
[111] Rebbeck, T.R.; Jaffe, J.M.; Walker, A.H.; Wein, A.J. and Malk-
owicz, S.B. (1998) J. Natl. Cancer Inst., 90(16), 1225-1229.
[112] Felix, C.A.; Walker, A.H.; Lange, B.J.; Williams, T.M.; Winick,
N.J.; Cheung, N.K.; Lovett, B.D.; Nowell, P.C.; Blair, I.A. and
Rebbeck, T.R. (1998) Proc. Natl. Acad. Sci. USA, 95(22), 13176-
13181.
[113] Wandel, C.; Witte, J.S.; Hall, J.M.; Stein, C.M.; Wood, A.J. and
Wilkinson, G.R. (2000) Clin. Pharmacol. Ther., 68(1), 82-91.
[114] Floyd, M.D.; Gervasini, G.; Masica, A.L.; Mayo, G.; George, A.L.
Jr.; Bhat, K.; Kim, R.B. and Wilkinson, G.R. (2003) Pharmacoge-
netics, 13(10), 595-606.
[115] Eap, C.B.; Buclin, T.; Hustert, E.; Bleiber, G.; Golay, K.P.; Aubert,
A.C.; Baumann, P.; Telenti, A. and Kerb, R. (2004) Eur. J. Clin.
Pharmacol., 60(4), 231-236.
[116] Baker, S.D.; van Schaik, R.H.; Rivory, L.P.; Ten Tije, A.J.; Dinh,
K.; Graveland, W.J.; Schenk, P.W.; Charles, K.A.; Clarke, S.J.;
Carducci, M.A.; McGuire, W.P.; Dawkins, F.; Gelderblom, H.;
Verweij, J. and Sparreboom, A. (2004) Clin. Cancer Res., 10(24),
8341-8350.
36 Current Drug Metabolism, 2006, Vol. 7, No. 1
[117] Ball, S.E.; Scatina, J.; Kao, J.; Ferron, G.M.; Fruncillo, R.; Mayer,
P.; Weinryb, I.; Guida, M.; Hopkins, P.J.; Warner, N. and Hall, J.
(1999) Clin. Pharmacol. Ther., 66(3), 288-294.
[118] Dai, D.; Tang, J.; Rose, R.; Hodgson, E.; Bienstock, R.J.; Mohren-
weiser, H.W. and Goldstein, J.A. (2001) J. Pharmacol. Exp. Ther.,
299(3), 825-831.
[119] Hsieh, K.P.; Lin, Y.Y.; Cheng, C.L.; Lai, M.L.; Lin, M.S.; Siest,
J.P. and Huang, J.D. (2001) Drug Metab. Dispos., 29(3), 268-273.
[120] Lamba, J.K.; Lin, Y.S.; Thummel, K.; Daly, A.; Watkins, P.B.;
Strom, S.; Zhang, J. and Schuetz, E.G. (2002) Pharmacogenetics,
12(2), 121-132.
[121] Eiselt, R.; Domanski, T.L.; Zibat, A.; Mueller, R.; Presecan-Siedel,
E.; Hustert, E.; Zanger, U.M.; Brockmoller, J.; Klenk, H.P.; Meyer,
U.A.; Khan, K.K.; He, Y.A.; Halpert, J.R. and Wojnowski, L.
(2001) Pharmacogenetics, 11(5), 447-458.
[122] van Schaik, R.H.; de Wildt, S.N.; Brosens, R.; van Fessem, M.; van
den Anker, J.N. and Lindemans, J. (2001) Clin. Chem., 47(6),
1104-1106.
[123] Ball, S.E.; Scatina, J.; Kao, J.; Ferron, G.M.; Fruncillo, R.; Mayer,
P.; Weinryb, I.; Guida, M.; Hopkins, P.J.; Warner, N. and Hall, J.
(1999) Clin. Pharmacol. Ther., 66(3), 288-294.
[124] Sata, F.; Sapone, A.; Elizondo, G.; Stocker, P.; Miller, V.P.; Zheng,
W.; Raunio, H.; Crespi, C.L. and Gonzalez, F.J. (2000) Clin.
Pharmacol. Ther., 67(1), 48-56.
[125] Walker, A.H.; Jaffe, J.M.; Gunasegaram, S.; Cummings, S.A.;
Huang, C.S.; Chern, H.D.; Olopade, O.I.; Weber, B.L. and
Rebbeck, T.R. (1998) Hum. Mutat., 12(4), 289.
[126] Fukushima-Uesaka, H.; Saito, Y.; Watanabe, H.; Shiseki, K.;
Saeki, M.; Nakamura, T.; Kurose, K.; Sai, K.; Komamura, K.;
Ueno, K.; Kamakura, S.; Kitakaze, M.; Hanai, S.; Nakajima, T.;
Matsumoto, K.; Saito, H.; Goto, Y.; Kimura, H.; Katoh, M.; Sugai,
K.; Minami, N.; Shirao, K.; Tamura, T.; Yamamoto, N.; Minami,
H.; Ohtsu, A.; Yoshida, T.; Saijo, N.; Kitamura, Y.; Kamatani, N.;
Ozawa, S. and Sawada, J. (2004) Hum. Mutat., 23(1), 100.
[127] Kuehl, P.; Zhang, J.; Lin, Y.; Lamba, J.; Assem, M.; Schuetz, J.;
Watkins, P.B.; Daly, A.; Wrighton, S.A.; Hall, S.D.; Maurel, P.;
Relling, M.; Brimer, C.; Yasuda, K.; Venkataramanan, R.; Strom,
S.; Thummel, K.; Boguski, M.S. and Schuetz, E. (2001) Nat.
Genet., 27(4), 383-391.
[128] Hustert, E.; Haberl, M.; Burk, O.; Wolbold, R.; He, Y.Q.; Klein,
K.; Nuessler, A.C.; Neuhaus, P.; Klattig, J.; Eiselt, R.; Koch, I.; Zi-
bat, A.; Brockmoller, J.; Halpert, J.R.; Zanger, U.M. and Wo-
jnowski, L. (2001) Pharmacogenetics, 11(9), 773-779.
[129] Lee, S.J.; Usmani, K.A.; Chanas, B.; Ghanayem, B.; Xi, T.; Hodg-
son, E.; Mohrenweiser, H.W. and Goldstein, J.A. (2003) Pharma-
cogenetics, 13(8), 461-472.
[130] Jounaidi, Y.; Hyrailles, V.; Gervot, L. and Maurel, P. (1996) Bio-
chem. Biophys. Res. Commun., 221(2), 466-470.
[131] Chou, F.C.; Tzeng, S.J. and Huang, J.D. (2001) Drug Metab. Dis-
pos., 29(9), 1205-1209.
[132] Lee, S.J.; Usmani, K.A.; Chanas, B.; Ghanayem, B.; Xi, T.;
Hodgson, E.; Mohrenweiser, H.W. and Goldstein, J.A. (2003)
Pharmacogenetics, 13(8), 461-472.
[133] Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y. and Guengerich,
F.P. (1994) J. Pharmacol. Exp. Ther., 270(1), 414-423.
[134] Chiou, W.L.; Jeong, H.Y.; Wu, T.C. and Ma, C. (2001) Clin.
Pharmacol. Ther., 70(4), 305-310.
[135] Rogers, J.F.; Rocci, M.L. Jr.; Haughey, D.B. and Bertino, J.S. Jr.
(2003) Clin. Pharmacol. Ther., 73(3), 153-158.
[136] Thummel, K.E.; Shen, D.D.; Podoll, T.D.; Kunze, K.L.; Trager,
W.F.; Hartwell, P.S.; Raisys, V.A.; Marsh, C.L.; McVicar, J.P. and
Barr, D.M. (1994) J. Pharmacol. Exp. Ther., 271(1), 549-556.
[137] Thummel, K.E.; O'Shea, D.; Paine, M.F.; Shen, D.D.; Kunze, K.L.;
Perkins, J.D. and Wilkinson, G.R. (1996) Clin. Pharmacol. Ther.,
59(5), 491-502.
[138] Watkins, P.B.; Turgeon, D.K.; Saenger, P.; Lown, K.S.; Kolars,
J.C.; Hamilton, T.; Fishman, K.; Guzelian, P.S. and Voorhees, J.J.
(1992) Clin. Pharmacol. Ther., 52(3), 265-273.
[139] Marre, F.; Sanderink, G.J.; de Sousa, G.; Gaillard, C.; Martinet, M.
and Rahmani, R. (1996) Cancer Res., 56(6), 1296-1302.
[140] Shou, M.; Martinet, M.; Korzekwa, K.R.; Krausz, K.W.; Gonzalez,
F.J. and Gelboin, H.V. (1998) Pharmacogenetics, 8(5), 391-401.
[141] Kamataki, T.; Yokoi, T.; Fujita, K. and Ando, Y. (1998) Cancer
Chemother. Pharmacol., 42(Suppl), S50-S53.
[142] Hirth, J.; Watkins, P.B.; Strawderman, M.; Schott, A.; Bruno, R.
and Baker, L.H (2000) Clin. Cancer Res., 6(4), 1255-1258.
Ken-ichi Fujita
[143] Yamamoto, N.; Tamura, T.; Kamiya, Y.; Sekine, I.; Kunitoh, H.
and Saijo, N. (2000) J. Clin. Oncol., 18(11), 2301-2308.
[144] Yamamoto, N.; Tamura, T.; Murakami, H.; Shimoyama, T.; Noki-
hara, H.; Ueda, Y.; Sekine, I.; Kunitoh, H.; Ohe, Y.; Kodam, T.;
Shimizu, M.; Nishio, K.; Ishizuka, N. and Saijo, N. (2005) J. Clin.
Oncol., 23(6), 1061-1069.
[145] Goh, B.C.; Lee, S.C.; Wang, L.Z.; Fan, L.; Guo, J.Y.; Lamba, J.;
Schuetz, E.; Lim, R.; Lim, H.L.; Ong, A.B. and Lee, H.S. (2002) J.
Clin. Oncol., 20(17), 3683-3690.
[146] Rougier, P.; Van Cutsem, E.; Bajetta, E.; Niederle, N.; Possinger,
K.; Labianca, R.; Navarro, M.; Morant, R.; Bleiberg, H.; Wils, J.;
Awad, L.; Herait, P. and Jacques, C. (1998) Lancet, 352(9138),
1407-1412.
[147] Kudoh, S.; Fujiwara, Y.; Takada, Y.; Yamamoto, H.; Kinoshita, A.;
Ariyoshi, Y.; Furuse, K. and Fukuoka, M. (1998) J. Clin. Oncol.,
16(3), 1068-1074.
[148] Negoro, S.; Fukuoka, M.; Masuda, N.; Takada, M.; Kusunoki, Y.;
Matsui, K.; Takifuji, N.; Kudoh, S.; Niitani, H. and Taguchi, T.
(1991) J. Natl. Cancer Inst., 83(16), 1164-1168.
[149] Mathijssen, R.H.; van Alphen, R.J.; Verweij, J.; Loos, W.J.;
Nooter, K.; Stoter, G. and Sparreboom, A. (2001) Clin. Cancer
Res., 7(8), 2182-2194.
[150] Santos, A.; Zanetta, S.; Cresteil, T.; Deroussent, A.; Pein, F.;
Raymond, E.; Vernillet, L.; Risse, M.L.; Boige, V.; Gouyette, A.
and Vassal, G. (2000) Clin. Cancer Res., 6(5), 2012-2020.
[151] Mathijssen, R.H.; de Jong, F.A.; van Schaik, R.H.; Lepper, E.R.;
Friberg, L.E.; Rietveld, T.; de Bruijn, P.; Graveland, W.J.; Figg,
W.D.; Verweij, J. and Sparreboom, A. (2004) J. Natl. Cancer Inst. ,
96(21), 1585-1592.
[152] Honig, P.K.; Wortham, D.C.; Zamani, K.; Conner, D.P.; Mullin,
J.C. and Cantilena, L.R. (1993) JAMA, 269(12), 1513-1518.
[153] Malingre, M.M.; Richel, D.J.; Beijnen, J.H.; Rosing, H.; Koopman,
F.J.; Ten Bokkel Huinink, W.W.; Schot, M.E. and Schellens, J.H.
(2001) J. Clin. Oncol., 19(4), 1160-1166.
[154] O'Brien, S.G.; Meinhardt, P.; Bond, E.; Beck, J.; Peng, B.; Dutreix,
C.; Mehring, G.; Milosavljev, S.; Huber, C.; Capdeville, R. and
Fischer, T. (2003) Br. J. Cancer, 89(10), 1855-1859.
[155] Dutreix, C.; Peng, B.; Mehring, G.; Hayes, M.; Capdeville, R.;
Pokorny, R. and Seiberling, M. (2004) Cancer Chemother. Phar-
macol., 54(4), 290-294.
[156] Frye, R.F.; Fitzgerald, S.M.; Lagattuta, T.F.; Hruska, M.W. and
Egorin, M.J. (2004) Clin. Pharmacol. Ther., 76(4), 323-329.
[157] Smith, P.F.; Bullock, J.M.; Booker, B.M.; Haas, C.E.; Berenson,
C.S. and Jusko, W.J. (2004) Blood, 104(4), 1229-1230.
[158] Bolton, A.E.; Peng, B.; Hubert, M.; Krebs-Brown, A.; Capdeville,
R.; Keller, U. and Seiberling, M. (2004) Cancer Chemother. Phar-
macol., 53(2), 102-106.
[159] Chang, S.M.; Kuhn, J.G.; Rizzo, J.; Robins, H.I.; Schold, S.C. Jr;
Spence, A.M.; Berger, M.S.; Mehta, M.P.; Bozik, M.E.; Pollack, I.;
Gilbert, M.; Fulton, D.; Rankin, C.; Malec, M. and Prados, M.D.
(1998) J. Clin. Oncol., 16(6), 2188-2194.
[160] Chang, S.M.; Kuhn, J.G.; Robins, H.I.; Schold, S.C. Jr.; Spence,
A.M.; Berger, M.S.; Mehta, M.; Pollack, I.F.; Rankin, C. and
Prados, M.D. (2001) Cancer, 91(2), 417-422.
[161] Rahmani, R.; Kleisbauer, J.P.; Cano, J.P.; Martin, M. and Barbet, J.
(1985) Cancer Treat. Rep., 69(7-8), 839-844.
[162] Rahmani, R.; Martin, M.; Favre, R.; Cano, J.P. and Barbet J. (1984)
Eur. J. Cancer Clin. Oncol., 20(11), 1409-1417.
[163] Zhou, X.J. and Rahmani, R. (1992) Drugs, 44(Suppl 4), 1-16.
[164] Villikka, K.; Kivisto, K.T.; Maenpaa, H.; Joensuu, H. and Neu-
vonen, P.J. (1999) Clin. Pharmacol. Ther., 66(6), 589-593.
[165] Oyama, T.; Morita, M.; Isse, T.; Kagawa, N.; Nakata, S.; So, T.;
Mizukami, M.; Ichiki, Y.; Ono, K.; Sugaya, M.; Uramoto, H.;
Yoshimatsu, T.; Hanagiri, T.; Sugio, K.; Kawamoto, T. and
Yasumoto, K. (2005) Front. Biosci., 10, 1156-1161.
[166] El-Rayes, B.F.; Ali, S.; Heilbrun, L.K.; Lababidi, S.; Bouwman,
D.; Visscher, D. and Philip, P.A. (2003) Clin. Cancer Res., 9(5),
1705-1709.
[167] Iscan, M.; Klaavuniemi, T.; Coban, T.; Kapucuoglu, N.; Pelkonen,
O. and Raunio, H. (2001) Breast Cancer Res. Treat., 70(1), 47-54.
[168] Yokose, T.; Doy, M.; Taniguchi, T.; Shimada, T.; Kakiki, M.;
Horie, T.; Matsuzaki, Y. and Mukai, K. (1999) Virchows. Arch.,
434(5), 401-411.
[169] Murray, G.I.; Taylor, V.E.; McKay, J.A.; Weaver, R.J.; Ewen,
S.W.; Melvin, W.T. and Burke, M.D. (1995) J. Pathol., 177(2),
147-152.
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 37

[170] Murray, G.I.; Weaver, R.J.; Paterson, P.J.; Ewen, S.W.; Melvin, [173] Miyoshi, Y.; Ando, A.; Takamura, Y.; Taguchi, T.; Tamaki, Y. and
W.T. and Burke, M.D. (1993) J. Pathol., 169(3), 347-353. Noguchi, S. (2002) Int. J. Cancer, 97(1), 129-132.
[171] Murray, G.I.; Shaw, D.; Weaver, R.J.; McKay, J.A.; Ewen, S.W.; [174] Jounaidi, Y.; Hecht, J.E. and Waxman, D.J. (1998) Cancer Res.,
Melvin, W.T. and Burke, M.D. (1994) Gut, 35(5), 599-603. 58(19), 4391-401.
[172] McKay, J.A.; Murray, G.I.; Weaver, R.J.; Ewen, S.W.; Melvin, [175] Jounaidi, Y. and Waxman, D.J. (2004) Cancer Res., 64(1), 292-
W.T. and Burke, M.D. (1993) Gut, 34(9), 1234-1239. 303.

Received: June 10, 2005 Revised: August 1, 2005 Accepted: August 4, 2005