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Cytochrome P450 and Anticancer Drugs: Ken-Ichi Fujita
Cytochrome P450 and Anticancer Drugs: Ken-Ichi Fujita
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.
reduced or absent ability to clear anticancer drugs compared ROLES OF CYPS IN METABOLISM OF ANTI-
to EM patients, resulting in higher plasma concentrations of CANCER DRUGS
the drugs and more toxic effects. The co-administration of
CYP enzymes are known to be involved in the metabo-
certain drugs or foods that modulate the activity of CYP en-
lism of a variety of anticancer drugs (Table 1). Specific iso-
zymes may lead to decreased metabolic clearance of antican-
forms responsible for the metabolism of each drug have been
cer agents due to the inhibition of drug-metabolizing en- identified through comprehensive in vitro experiments. Since
zymes or to increased clearance due to enzyme induction. species differences in drug metabolism by CYPs have been
The decrement of metabolic clearance of anticancer agents well documented, human CYP preparations should be used.
may result in adverse drug reactions, while increased clear- The metabolism of paclitaxel, for example, may be a case
ance may cause insufficient tumor suppressive effects. Both
demonstrating the remarkable species differences in CYP-
consequences can be severe.
mediated metabolism between rats and humans [6, 7]. One of
Research related to the metabolism and pharmacokinetics major metabolites produced by human CYP2C8 (6α-
of cancer chemotherapeutic agents has been reviewed [1, 2, hydroxypaclitaxel) was not observed in rat bile. The in vitro
4, 5], and it is increasingly apparent that the individualization systems derived from human tissue developed to date in-
of the chemotherapy should take account of the factors that clude subcellular fractions (liver microsomes, cytosols and
modify the metabolism and pharmacokinetics of anticancer homogenates), precision-cut liver slices, and hepatocytes [8-
agents. 18]. Besides these systems, genetically engineered cells ex-
In this review the roles of CYP enzymes in the metabo- pressing human CYPs have been established. Various host
lism of anticancer drugs will be first described. Then, the cells are used for the heterologous expression of CYP iso-
effects of the variability of CYP activities on the interindi- forms. Among them, bacterial cells such as Escherichia coli
vidual variations of pharmacokinetic profiles of anticancer and Salmonella typhimurium have advantages with regard to
drugs will be discussed. the ease of use and the high yield of protein [16-18].
N-Dechloroethylation 43
N-Dechloroethylation 43
Docetaxel Hydroxylation 63
N-Dechloroethylation 43
Teniposide O-Demethylation 21
Tamoxifen paclitaxel, was present in both human and rat bile. On the
other hand, one of the major metabolites present in human
The selective estrogen receptor modulator, tamoxifen, bile, 6α-hydroxypaclitaxel, was not present in the rat bile
has been widely used for more than 25 years for the endo- [61], indicating species differences in the biotransformation
crine treatment of all stages of hormone receptor–positive of paclitaxel between rats and humans. The biotransforma-
breast cancer [47]. Tamoxifen is also approved by the United
tion of paclitaxel by human liver was investigated in vitro
States Food and Drug Administration for the prevention of with liver microsomes isolated from adults. Cresteil et al. [6]
breast cancer in women at high risk for developing the dis-
first concluded that CYP2C accounted for the formation of
ease [48].
6α-hydroxypaclitaxel, which was the major metabolite
Jordan et al. [49] demonstrated that hepatic metabolism formed in vivo and in vitro, while CYP3A supported the 3’-
of tamoxifen resulted in a statistically significant increase in p-hydroxypaclitaxel formation. Subsequently, Rahman et al.
its efficacy in vivo; they also showed for the first time that 4- [62] demonstrated that 6α-hydroxypaclitaxel formation from
hydroxytamoxifen, one of the human tamoxifen metabolites, paclitaxel was catalyzed by CYP2C8.
was approximately 100 times more potent than tamoxifen as In contrast to paclitaxel, the biotransformation pathway
an estrogen antagonist in vitro. The tamoxifen metabolite N- of docetaxel is similar in animals and humans. The initial
desmethyltamoxifen is 100 times less active than tamoxifen metabolite resulted from the hydroxylation of the methyl of
in vitro [50], although it is more abundant in plasma of pa- the tert-butyl group at the C 13 side chain of docetaxel. Royer
tients receiving tamoxifen treatment than tamoxifen itself. et al. [63] have documented that docetaxel hydroxylation
Recently, the activity of another tamoxifen metabolite, en- was catalyzed by human CYP3A, based on the correlation of
doxifen (4-hydroxy-N-desmethyltamoxifen), which is pre- the metabolism with CYP3A-dependent 6β-hydroxylation of
sent at notably higher concentrations than 4-hydroxytamox- testosterone and 16-hydroxylation of dehydroepiandroster-
ifen in the plasma of breast cancer patients receiving chronic one, and inhibition with CYP3A inhibitors.
tamoxifen therapy was characterized [51]. In a series of in
vitro studies [51], endoxifen exhibited the same potency and Thalidomide
efficacy as 4-hydroxytamoxifen in suppressing estrogen-
dependent breast cancer cell growth and gene expression. Thalidomide is an old compound that was originally de-
veloped as a sedative. The drug was eventually withdrawn
Tamoxifen is metabolized extensively by human liver from the general market because of its severe adverse effect
enzymes to primary and secondary metabolites [51-53]. A of teratogenesis. It has been reintroduced over the past sev-
comprehensive kinetic characterization of tamoxifen se- eral years in the treatment of leprosy. More recently, the drug
quential metabolism in vitro demonstrated that CYP3A is the has been found to be effective against various diseases in-
major CYP subfamily responsible for the formation of N- cluding multiple myeloma and prostate cancer, at least in
desmethyltamoxifen, whereas the generation of 4-hydroxy- part, through the inhibition of angiogenesis [64-66]. Results
tamoxifen and endoxifen appeared to be predominantly obtained so far suggested that thalidomide requires CYP
catalyzed by CYP2D6. catalyzed biotransformation to exert its pharmacological
Although tamoxifen therapy is associated with benefits activities including antiangiogenesis [67-69], though the
for breast cancer, it is also associated with several adverse exact mechanism of action has not been well clarified. Al-
events, including endometrial cancer [54]. Shibutani and though thalidomide is subject to spontaneous nonenzymatic
colleagues [55-58] demonstrated that a hydroxylated ta- hydrolysis, these breakdown products may not be responsi-
moxifen metabolite, α-hydroxytamoxifen, produced by hu- ble for the pharmacological activity [70]. The hydroxylated
man CYP3A was further metabolized by sulfotransferases to metabolites, 5-hydroxythalidomide, cis- and trans-5’hyd-
form an O-sulfonated metabolite that produced tamoxifen- roxythalidomide, have been found in plasma or urine of pa-
DNA adducts. The tamoxifen-DNA adducts were detected in tients [71, 72]. Recently, it has been reported that CYP2C19
the endometrium of women taking tamoxifen. These results is predominantly involved in the 5- and 5’-hydroxylation of
suggest the α-hydroxytamoxifen may be responsible for the thalidomide in humans [73].
adverse carcinogenic effects of tamoxifen.
Tegafur
Taxanes Tegafur is a prodrug of 5-fluorouracil (5-FU) synthesized
Taxanes are a family of structurally related compounds more than 30 years ago. The anticancer drug has been clini-
that share a core ring structures referred to as baccatin III. cally used for the treatment of mainly gastric and colon can-
Two members of this family, paclitaxel and docetaxel, are cers because of the lower toxicity than 5-FU. 5-FU exerts its
important anticancer drugs extensively used in the treatment cytotoxic effects via the inhibition of thymidylate synthase
of various malignancies including ovarian cancer, breast and/or its incorporation into RNA molecules. The active
cancer and lung cancer [59]. compound, 5-FU, is then further metabolized by dehydro-
pyrimidine dehydrogenase to form inactive metabolites. Te-
The metabolism of paclitaxel has been studied in both gafur is converted to 5-FU mainly in the liver through an
rats and human patients [6, 7]. The results showed that pa- unstable intermediate, 5’-hydroxytegafur. The formation of
clitaxel metabolites observed in the bile of a human patients 5-FU from tegafur is known to be mainly catalyzed by hu-
were mostly different from those observed in rat bile [6, 7]. man CYP2A6 [74] as shown in experiments with human liver
Nine metabolites were detectable in rat bile [60] and in five microsomes that revealed a significant correlation between
metabolites were in the bile of a patient with metastatic cho- 5-FU formation from tegafur and 7-hydroxylation of cou-
langiocarcinoma [61]. Only one metabolite, 3’-p-hydroxy- marin, a representative metabolic reaction for CYP2A6.
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 27
Canadian
African-
Caucasian Japanese Korean Chinese Native
American
Indean
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*4B) 0.24
(CYP2A6*4D) 0 0.5
CYP2A6*6 0 0
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*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 moxifen to breast cancer patients depends on the CYP2D6
endoxifen concentrations that were 26% of those of subjects genotype. The results of definitive clinical trials that include
having the wild CYP2D6 genotype. Although, Jin et al. still outcomes such as breast cancer recurrence and mortality,
did not show direct evidence indicating the relationship be- toxicity and secondary benefits are awaited. CYP2D6 allele
tween the efficacy of tamoxifen and CYP2D6 genotype, frequencies are shown in Table 3.
these results may suggest that the clinical benefit of ta-
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 29
Saudi
Caucasian European German Russian Spaniad Japanese Chinese Zimbabwean Ethiopian
Arabian
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*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*11 0 0.1
CYP2D6*12 0 0.1
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
CYP3A4*1
(CYP3A4*1A) 73.4
(CYP3A4*1G) 18.9
(CYP3A4*1H) 1
CYP3A4*2 0 2.7 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*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*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*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
Phenotypic Variation of CYP3A4 Activity Related to Extensive attempts have been made to manipulate the
Pharmacokinetics of Anticancer Drugs large variation of CYP3A4 activity and to reduce pharma-
cokinetic variability of the relevant drugs. Since the genetic
The enzyme activity of CYP3A4, which is responsible variations seen in CYP3A4 are estimated to be small as
for the biotransformation of a wide variety of anticancer
mentioned above, phenotyping strategies to predict an indi-
drugs (Table 1), exhibits a remarkable interindividual varia- vidual’s CYP3A activity before cytotoxic chemotherapy
tion as high as 20 to 40 fold [108, 133]. In addition to the treatment could be an appropriate approach for dose indi-
large variation caused by the difference of constitutive ex- vidualization. Various noninvasive in vivo probes for evalu-
pression, CYP3A4 expression is affected by the concomitant ating CYP3A activity have been described and several have
intake of CYP3A4 inducers such as rifampicin. The co- been shown to correlate with drug clearance [134-138]. The
administration of therapeutic drugs which can modulate the most widely tested and accepted CYP3A probes are midazo-
CYP3A4 activity can alter the metabolism of anticancer
lam, erythromycin and cortisol, although selection of the
drugs. It has been recently reported that liver function to- ideal CYP3A-probe remains controversial [134-138].
gether with the concentration of the acute-phase reactant, α-1
acid glycoprotein, explained up to 18% of overall variation in Docetaxel, which is mainly metabolized by CYP3A4 in
CYP3A activity [116]. humans [63], shows large interindividual variability in its
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 31
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*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
pharmacokinetic/pharmacodynamic profiles [139, 140]. The domized study, they examined whether individualized dosing
effects of inhibition and induction of CYP3A on docetaxel via CYP3A phenotyping could decrease the pharmacoki-
pharmacokinetics was investigated in mice [141]. Pretreat- netic/pharmacodynamic variability of docetaxel compared to
ment of mice with the CYP3A inhibitor, ketoconazole, in- more routine BSA-based dosing [144]. Fifty-nine patients
creased the AUC of docetaxel, whereas treatment with the with advanced non-small cell lung cancer were randomly
CYP3A inducer, dexamethasone, decreased the AUC of do- assigned to either the BSA-based arm or the individualized
cetaxel. These findings suggest that enzymatic inhibition and arm. In the BSA-based arm, 60 mg/m2 of docetaxel was ad-
induction of CYP3A might affect docetaxel pharmacokinet- ministered. In the individualized arm, the doses of docetaxel
ics and its antitumor potency in humans. were calculated from the estimated clearance and a target
AUC of 2.66 mg·h/L. The standard deviation of the AUC
Attempts have been made to quantify the phenotypic
was significantly smaller in the individualized arm than in
activity of CYP3A4 and to evaluate the correlation between
the activity and the pharmacokinetic parameters of do- the BSA-based arm. The respective percentage decreases in
cetaxel. In a study with 21 sarcoma patients who were absolute neutrophil counts were 87.1±8.7% in the BSA-
treated with 100 mg/m2 of docetaxel, the erythromycin based arm and 87.4±6.1% in the individualized arm. The
breath test (ERMBT) using [ 14C-N-methyl]erythromycin was results indicate that the interpatient variability in percent
employed to measure hepatic CYP3A activity in vivo [142]. decreases in absolute neutrophil counts was slightly smaller
The natural log of ERMBT accounted for 67% of the inter- in the individualized arm. In another study, docetaxel clear-
ance was found to be correlated with midazolam clearance
patient variability in the docetaxel clearance. In another
[145].
study, Yamamoto et al. [143] measured urinary 6β-
hydroxycortisol in 30 patients with non-small cell lung can- These studies suggest that CYP3A4 activity could be a
cer treated with 60 mg/m2 docetaxel after the administration useful indicator to predict in vivo docetaxel clearance and
of the 300 mg of hydroxycortisone. Cortisol is selectively toxicity, and that CYP3A4-guided dosing could be a useful
metabolized by CYP3A and excreted in the urine as 6β- method for docetaxel dosing.
hydroxycortisol [138]. They used 300 mg of exogenous cor- Irinotecan is a camptothecin analogue with potent antitu-
tisone, since the amount of 6β-hydroxycortisol produced
mor activity resulting from inhibition of topoisomerase I. It
from endogenous cortisol was too low to be sensitively de- is widely used for the treatment of colorectal and lung can-
tected in urine. Multivariate analysis revealed that the total cers [146-148]. Pharmacokinetic variability of irinotecan
amount of 24 h urinary 6β-hydroxycortisol was the strongest
among patients is also large. Pathways that eliminate irinote-
factor predicting docetaxel clearance. In a subsequent ran-
32 Current Drug Metabolism, 2006, Vol. 7, No. 1 Ken-ichi Fujita
can include CYP3A, carboxylesterase, UGT1A1, and drug- mg of imatinib once daily orally and on study day 8, 400 mg
transporting proteins [149]. CYP3A4 was reported to play a imatinib together with 40 mg of simvastatin was given.
role in irinotecan metabolism, though CYP3A5 did not Imatinib increased the mean maximum concentration
[150]. Mathijssen et al. [151] demonstrated a correlation (Cmax) value of simvastatin two-fold and the AUC value
between irinotecan and midazolam clearance. Because dos- 3.5-fold compared with simvastatin alone. Recently, the ef-
ing strategies that were based on BSA did not reduce the fect of ketoconazole, a potent CYP3A inhibitor, on the
interindividual variability in irinotecan pharmacokinetics, pharmacokinetics of imatinib was investigated [155]. Each
they recommended evaluating midazolam clearance com- subject received a single oral dose of imatinib 200 mg alone,
bined with the UGT1A1*28 polymorphism for optimizing and a single oral dose of imatinib 200 mg co-administered
irinotecan chemotherapy. The active irinotecan metabolite, with a single oral dose of ketoconazole 400 mg according to
SN-38, is further processed by glucuronidation. Their results a two-period crossover design. Following ketoconazole co-
supported the idea that a CYP3A-guided strategy is applica- administration, the mean imatinib Cmax and AUC increased
ble for dosing anticancer drugs that are mainly metabolized significantly by 26 and 40%, respectively. There was a sta-
by CYP3A. tistically significant decrease in apparent clearance of
imatinib with a mean reduction of 28.6%. These interactions
Drug Interactions Relevant to Anticancer Drugs should be considered when administering substrates or in-
hibitors of the CYP3A family in combination with imatinib.
Metabolic drug-drug interactions occur when one drug
Conversely, co-administration of rifampicin and St John’s
alters the activity of a drug-metabolizing enzyme, thereby
wort, which are potent inducers of CYP3A4, decreased the
affecting the pharmacokinetics of drugs metabolized by the Cmax and AUC of imatinib in healthy volunteers [156-158].
enzyme. Various interactions have been reported thus far. Therefore, the concomitant use of enzyme inducers may ne-
For example, the metabolism of terfenadine by human cessitate an increase in the imatinib dose to maintain clinical
CYP3A is known to be inhibited by azole antifungal drugs,
effectiveness.
causing a notable increase in the plasma concentration of the
parent drug causing severe adverse drug reactions associated
Paclitaxel
with prolongation of the corrected QT interval in humans
[152]. The co-administration of drug(s) with anticancer Glioma patients commonly receive anticonvulsants such
drugs has also been reported to induce drug interactions by as phenytoin, phenobarbital and carbamazepine and corti-
modifying their pharmacokinetic properties. Although, drug costeroids that may increase the hepatic metabolism of pa-
interactions are generally considered to cause adverse drug clitaxel by CYPs. A Phase I study to determine the MTD of
reactions, they sometimes might cause benefits such as an paclitaxel administration as a 3 h infusion in patients with
improvement in drug bioavailability. For example, the inhi- recurrent malignant glioma was performed [159]. The MTD
bition of CYPs in the small intestine may result in the eleva- for patients who received anticonvulsants was established to
tion of the bioavailability of drugs which are orally adminis- be 360 mg/m2, whereas the MTD for patients who did not
tered. receive anticonvulsants was 210 mg/m2. Pharmacokinetic
data demonstrated that the plasma paclitaxel levels and
Docetaxel clearance rates were similar for patients in both groups at
respective dose levels that produced dose-limiting toxicity.
A proof-of-concept study was carried out in 14 patients
These results indicate that the pharmacokinetics of paclitaxel
with solid tumors [153]. In one course, patients received oral
are altered by the co-administration of anticonvulsants, and
docetaxel of 75 mg/m2 with or without a single oral dose of
significantly larger doses of the drug can be administered to
cyclosporine A (15 mg/kg). During subsequent courses, pa-
patients with brain tumors who require anticonvulsants. Sub-
tients received 100 mg/m2 of intravenous docetaxel. The sequently, a Phase II study to confirm the effects of pacli-
AUCs seen in patients who received oral docetaxel 75 mg/m2
taxel on recurrent malignant glioma was performed using
with and without cyclosporine A were 2.71 ± 1.81 and 0.37 ± doses determined in the Phase I study. Unfortunately, no
0.33 mg·h/L, respectively. The absolute bioavailability of
objective clinical response to any dose of paclitaxel for re-
oral docetaxel observed with or without cyclosporine A, current malignant glioma was observed [160].
which was calculated from the mean AUC of intravenous
docetaxel, was 90 ± 44 or 8 ± 6%. Co-administration of oral Tamoxifen
cyclosporine A strongly enhanced the oral bioavailability of
docetaxel. These data may form the basis for the further de- Jin et al. [95] demonstrated the effects of selective sero-
velopment of a clinically useful oral formulation of do- tonin reuptake inhibitors (SSRIs) that were also inhibitors of
cetaxel. CYP2D6 on the plasma level of endoxifen. SSRIs are com-
monly prescribed to treat hot flashes in breast cancer patients
Imatinib who take tamoxifen. The concomitant administration of
SSRIs such as paroxetine substantially reduced the plasma
Pharmacokinetic interactions of imatinib with substrates concentration of endoxifen, suggesting a potential alteration
and inhibitors of CYP3A4 have been studied. O’Brien et al.
in the expression of tamoxifen activity.
[154] have evaluated the effect of the co-administration of
imatinib on the pharmacokinetics of simvastatin, a probe
Vincristine
CYP3A4 substrate. In total, 20 patients with chronic myeloid
leukemia received an oral dose of 40 mg simvastatin on Although vinca alkaloids show similarity in their chemi-
study day 1. On study days 2-7, each patient received 400 cal structures, they exhibit marked differences in their re-
Cytochrome P450 and Anticancer Drugs Current Drug Metabolism, 2006, Vol. 7, No. 1 33
spective antitumor spectra, toxicity and pharmacokinetics been developed in animal models. A CYP2B6 gene coding
[161-163]. Moreover, their clinical pharmacokinetics shows for the enzyme that is responsible for the activation of cyclo-
large intra- and/or inter-individual variations. Since these phosphamide has been transferred into tumor cells with a
agents are metabolized by CYP3A, it may be possible that retrovirus and replication-conditional adenovirus to enhance
the variability of CYP3A activity is partly responsible for the the intratumoral activation of prodrugs [174, 175].
variation in the pharmacokinetic profiles of vinca alkaloids.
The effects of the CYP3A4-inducing antiepileptic agents, PERSPECTIVES
carbamazepine and phenytoin, on the pharmacokinetics of Generally, for select drugs whose pharmacokinetic/phar-
vincristine have been studied [164]. Fifteen adult patients macodynamic relationships are known, feedback control of
with brain tumors receiving combination chemotherapy with plasma concentrations, through therapeutic drug monitoring
procarbazine, lomustine, and vincristine volunteered for this (TDM), may be invoked to minimize the variability in their
open parallel-group study. Nine of the patients used either therapeutic and toxic effects. However, for cancer che-
carbamazepine or phenytoin and six of the patients used no motherapeutic agents, TDM cannot be readily used to reduce
obvious CYP3A4-inducing medication. The results revealed pharmacokinetic/pharmacodynamic variations because of the
that drugs inducing CYP3A4 could increase the elimination following reasons:
of vincristine. Further studies are needed to determine
whether the increased clearance of vincristine by carba- § The pharmacokinetic/pharmacodynamic relationships are
not well known;
mazepine or phenytoin decreases the efficacy of vincristine.
§ The threshold of the antitumor effects is usually obscure
Local Expression of CYPs in Tumor Tissues and dependent on the patient factors, which may not be
well quantified;
Recently, a number of cancer tissues have been found to
express a variety of CYPs [165-172]. The local expression of § There is a long time lag between the treatment of patients
CYPs in tumor tissues appears to be important for tumor with anticancer drugs and the appearance of the efficacy
management, since CYPs expressed in tumors may be re- of the drugs (a large time constant);
sponsible for the localized inactivation and/or activation of
§ It is difficult to determine the target drug to be monitored
anticancer drugs. Inactivation of anticancer drugs by CYPs
because most cancer chemotherapeutics is based on in-
in tumor tissues may result in the resistance of the tumor
tentional polypharmacy; of the combination use of anti-
toward the drugs, while the activation of prodrugs by CYPs
cancer drugs;
may lead to the enhancement of effectiveness in cancer che-
motherapy. As shown in Table 1, CYP2A, CYP2B, CYP2C, § Dose adjustments may be difficult to make in chemother-
CYP2D and CYP3A are mainly responsible for the metabo- apy once dose-limiting toxicity thresholds have been
lism of anticancer drugs. These forms of CYP have been reached.
reported to be expressed in tumor tissues. CYP2A6 was
found to be expressed in breast cancer tissue obtained from a Therefore, the optimal dose of anticancer drugs should,
Japanese patient (among 34 patients) [165]. CYP2B6 was when possible, be established prior to drug administration.
demonstrated to be present in breast tumor tissues [166, Since CYP forms are responsible for the metabolism of a
167]. CYP2C enzymes were expressed in 33% of breast can- wide variety of anticancer drugs and these enzymes show a
cer tissues and 25% of prostate cancer tissues [168, 169]. vast range of variability in their activities due to genetic and
The expression of CYP2D6 in breast tumors has been re- nongenetic factors, CYP activity should be a good biomarker
ported by Iscan et al. [167]. CYP3A was found in 22% of for establishing individualized doses of anticancer drugs.
breast cancer by immunohistochemistry [170], however, the This is a feedforward concept for the determination of indi-
enzyme was not detected in 34 specimens from Japanese vidualized doses of anticancer drugs. Tests of this new con-
patients [165]. Murray et al. [171] have shown that CYP3A cept for initializing/optimizing chemotherapy are now in
was expressed in at least 60% of oesophageal carcinomas. progress.
CYP3A has been also reported to be expressed in colon car-
cinomas and prostate cancer [169, 172]. ABBREVIATIONS
It seems likely that there is a large interindividual vari- AUC = Area under the concentration-time curve
ability in CYP expression in tumor tissues. This may also BSA = Body surface area
contribute to the interindividual variability in the response to
chemotherapy. Indeed, Miyoshi et al. [173] demonstrated Cmax = Maximum concentration
that intratumoral expression of CYP3A4 mRNA was signifi- CYP = Cytochrome P450
cantly lower (about 4 fold) in responders compared with
nonresponders in docetaxel treatment. Further studies are ERMBT = Erythromycin breath test
needed to clarify the roles of CYPs expressed in tumor tis- 5-FU = 5-Fluorouracil
sues in cancer chemotherapy.
MTD = Maximum-tolerated dose
One therapeutically attractive strategy to enhance the
intratumoral activation of a prodrug is based on the direct SSRI = Selective serotonin reuptake inhibitor
transfer to the tumor of a gene which encodes an enzyme that
can activate the prodrug, and this gene therapy strategy has TK = Tyrosine kinase
34 Current Drug Metabolism, 2006, Vol. 7, No. 1 Ken-ichi Fujita
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Received: June 10, 2005 Revised: August 1, 2005 Accepted: August 4, 2005