Principles of Drug Biotransformation

Section 1
Chapter
Principles of drug action
Principles of drug biotransformation
6 Evan D. Kharasch
transport is sometimes referred to as phase III metabolism.

Introduction Metabolism and transport together influence drug bioavailability,
This chapter will present clearance concepts, biotransformation elimination, and clinical response, but transporters do not cata-
reactions, pathways of metabolism (phase I reactions including lyze metabolism per se, and are presented elsewhere (Chapter 7).
oxidation, hydrolysis, reduction, and dehydrogenation; and
phase II reactions including glucuronidation, sulfation, acetyla-
tion, and glutathione conjugation), and the expression, activity, Consequences of anesthetic
regulation, ontogeny, interindividual variability, and genetics of
drug metabolism. The focus will be on humans, because drug
metabolism
metabolism pathways and enzymes often differ significantly in Anesthetic metabolism can have several consequences
animals, both qualitatively and quantitatively. The liver is the (Fig. 6.1). An active drug can be converted to an inactive
predominant site of biotransformation, but increasingly import- metabolite, such as metabolism of fentanyl to norfentanyl.
ant extrahepatic (intestinal, renal, brain, blood) metabolism will Although typically considered mainly as a route of drug
also be presented. Finally, the role of biotransformation in drug inactivation, metabolism can have several other conse-
response will be presented. quences. An active drug can be converted to a pharmaco-
Drug metabolism is often intimately involved with drug logically active metabolite. For example, the primary (phase I)
transport, because drug uptake and efflux from intestinal, metabolite of midazolam, 1-hydroxymidazolam, possesses
hepatic, and renal cells determines the size of the intracellular considerable pharmacologic activity and contributes to the
drug pool which is available for metabolism. Indeed, drug clinical effect of the parent drug. The phase II metabolite of
Drug or Active Inactive Figure 6.1. Consequences of drug biotransfor-

Inactive Prodrug Prodrug Metabolite Active Metabolite Metabolite Toxic Metabolite mation. Drugs which may be an active metabolite
fentanyl norfentanyl or administered directly (e.g., propofol) are shown
methadone EDDP in red.
lorazepam lorazepam
glucuronide
midazolam 1-OH-midazolam
1-OH-midazolam glucuronide
diazepam nordiazepam oxazepam oxazepam
temazepam glucuronide
codeine morphine morphine-6-glucuronide
normorphine
norcodeine
codeine
glucuronide
fospropofol propofol propofol
glucuronide
meperidine normeperidine
halothane trifluoroacetic
acid
trifluoroacyl
chloride
Anesthetic Pharmacology, 2nd edition, ed. Alex S. Evers, Mervyn Maze, Evan D. Kharasch. Published by Cambridge University Press. # Cambridge University Press 2011.
72
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Chapter 6: Principles of drug biotransformation
A Primary blockers), hepatic clearance (CLH), defined as the volume of blood

elimination Hepatic CYP
route
from which drug is completely removed by the liver per unit time,
enzyme isoform
100% Not 1A2 (9%)
is a major route of elimination [4]. Hepatic clearance is the
known product of hepatic blood flow (QH) and the hepatic extraction
1 2 n
2A6 (1%)
w
er a s e n o
2B6 (4%)
O Ph Un
k 2C8 (6%)
ratio (EH) of a drug:
80% Φ
CLH ¼ QH EH ð6:1Þ
th
2C9 (17%)
EH is defined as the fraction of drug in the blood entering the
60% 2C19 (10%) liver which is irreversibly eliminated during one pass through
Hepatic the liver.
2D6 (15%)
40% CYP Cin Cout
2E1 (1%) EH ¼ ð6:2Þ
Cin
20% As shown in Eq. 6.3, EH depends on liver blood flow and the
3A4/5 (37%)
Renal intrinsic clearance of unbound drug (CLint), defined as the
total capacity of the liver to eliminate drug in the absence of
0% limitations from blood flow:

CLint
B % of total hepatic P450 % of total intestinal P450 EH ¼ ð6:3Þ
QH þ CLint
2B6
2C8 CLint functionally represents drug biotransformation (the total
2A6 activity of enzymes and transporters involved in drug metab-
2C9 olism and biliary secretion). Thus, combining Eqs. 6.3 and 6.1:
1A2 2C19
2C9
2C19 CLint
2D6
2D6 CLH ¼ QH ð6:4Þ
3A4 2J2 QH þ CLint
2E1
3A4/5 Since only unbound drug is considered diffusable into liver
cells (although in reality a simplification) [5], EH also depends
on the fraction of unbound drug in blood (fu). Hence the three
Figure 6.2. (A) Organs and enzymes of drug elimination. Data are shown for primary determinants of hepatic drug clearance are (1) hepatic
the top 200 prescription drugs in the USA according to the RxList data, April, blood flow, (2) drug binding in blood (typically plasma protein
2008 (www.rxlist.com). Hepatic enzymes are cytochrome P450 (CYP); other binding), and (3) intrinsic clearance (biotransformation):
phase I enzymes (Φ1, esterases, flavin monooxygnase, N-acetyl transferase,
monoamine oxidase), and phase II enzymes. The percentage of drugs metabol- CLint fu
ized by a CYP isoform are shown in parentheses. Redrawn with permission from CLH ¼ QH EH ¼ QH ð6:5Þ
Zanger et al. [1]. (B) Content of cytochrome P450 isoforms in human liver and QH þ CLint fu
intestine. Based on data from Rowland-Yeo et al. [2] and Paine et al. [3].
Orally administered drugs traverse two organs of biotransforma-
tion, the small intestine and the liver, before reaching the sys-
morphine, morphine-6-glucuronide, is a clinically effective
temic circulation (Fig. 6.3) [6]. Traditionally thought of as an
m-opioid receptor agonist. An inactive prodrug can be bioacti-
organ of absorption, the small intestine also has considerable
vated to an active metabolite, such as the amide hydrolysis of
drug metabolizing activity, involving both phase I and phase II
the inactive precursor parecoxib to the active COX-2 selective
reactions [7,8]. Oral drug bioavailability is the fraction of admin-
inhibitor valdecoxib, conversion of fospropofol to propofol, or
istered drug which enters the systemic circulation. Bioavailability
the oxidation of inactive codeine to the more active metabolite
(F) after oral administration is the product (not the sum) of the
morphine. Phase I or II reactions can also convert a drug to a
individual bioavailabilities in each successive organ, hence:
toxic metabolite, such as the N-demethylation of meperidine to
normeperidine, which can cause seizures. F ¼ fabs FGI FH ¼ fabs ð1 EGI Þ ð1 EH Þ ð6:6Þ
where fabs is the fraction of drug absorbed across the gut
Basic clearance concepts lumen, EGI and EH are the intestinal and hepatic extraction
ratios, and FGI and FH are the intestinal (gut) and hepatic
Total-body drug clearance represents the sum of hepatic clear- bioavailabilities, respectively (F ¼ 1 – E).
ance, renal clearance, and, for some drugs, other routes of Bioavailability can be reduced by both intestinal and
clearance (such as pulmonary elimination of volatile anesthetics) hepatic biotransformation (which act in series), referred to
(Fig. 6.2A) [1]. For most drugs, including those used in anesthesia as first-pass, or presystemic, metabolism. First-pass meta-
(sedative-hypnotics, benzodiazepines, opioids, neuromuscular bolism can occur in the intestine, the liver, or both organs.
73
Section 1: Principles of drug action
1) Hepatocytes of the liver Figure 6.3. Metabolism of a theoretical drug after

Foral = FGI × FH intravenous and oral administration. (A) An intraven-
100% B
= 30% × 50% ously injected drug is eliminated in the liver, where
= 15% it undergoes metabolism by CYP3A4 and/or trans-
15% 15% port by P-glycoprotein (P-gp) in hepatocytes (1). The
hepatic extraction ratio (EH) is 0.5, and therefore
CYP3A4 hepatic availability (1 – EH) is 0.5 (50%) after each
passage of blood through the liver. (B) The orally
P-gp
30% 2) Enterocytes of the small intestine administered drug undergoes sequential first-pass
1
elimination by CYP3A4 metabolism and/or transport
100% by P-gp in enterocytes of the small intestine (2) and
then hepatocytes of the liver (1). The intestinal
Sinusoid extraction ratio (EGI) is 0.7, and therefore intestinal
100% availability (1 – EGI) is 0.3 (30%). Although the drug is
Hepatic availability
P-gp CYP3A4 100% absorbed from the gastrointestinal tract, the
FH = 1 – EH = 50% 2 oral bioavailability is only 15%. Adapted with per-
30%
mission from Bailey and Dresser [6].
Intestinal availability
Gut
FGI = 1 – EGI = 30%
A Lumen
Intestinal extraction can range from < 1% to > 99%, but can oxidations, which involve the initial insertion of an oxygen atom.
be particularly important for drugs with high first-pass Oxygen remains on the drug molecule with hydroxylation reac-
clearance and low oral bioavailability. Low oral bioavailabil- tions, and leaves on the alkyl group as the aldehyde with deal-
ity, once attributed only to hepatic first-pass extraction, is kylation reactions. Phase I oxidative reactions include aromatic
now known to result also from a quantitatively significant and aliphatic hydroxylation, O- and N-dealkylation (of which
component of intestinal first-pass extraction. Intestinal N-demethylation is a subset), epoxidation, and oxidative deami-
metabolism plays a relatively minor role in systemic drug nation and dehalogenation. N- and S-oxidation may also occur.
elimination. Reduction is another type of phase I reaction, often under
anaerobic conditions. Some drugs may undergo both oxida-
tion and reduction, depending on the oxygen tension. For
Basic drug metabolism concepts example, halothane undergoes (1) oxidation to a trifluoroacyl
Several recent reviews and textbooks provide a comprehensive halide which can subsequently react with liver proteins to form
perspective on drug biotransformation [1,9–14]. A more trifluoroacetylated protein neoantigens, and (2) anaerobic
in-depth, multi-part review is also available [15]. reduction to a free radical which gives rise to chlorodifluor-
Therapeutic drugs, whether natural products or syn- oethylene and chlorotrifluoroethane. Hydrolysis is a phase
thetic, tend to be relatively lipophilic because they typically I reaction that is not catalyzed by CYP, but is catalyzed by
must traverse one or more plasma membranes to reach their esterases/amidases.
site of action. In general, biotransformation reactions con-
vert compounds to more polar hydrophilic molecules that
are more amenable to excretion, generally via the kidney. Enzymes of metabolism
Traditionally, biotransformation reactions have been cat-
egorized as phase I and phase II reactions. The former are Phase I enzymes
termed functionalization reactions, which introduce or Cytochrome P450
uncover a functional group (hydroxyl, amine, acid) that Cytochrome P450 (CYP) is the main drug-metabolizing
moderately increases drug polarity and prepares it for a enzyme system (Fig. 6.2A) [1,16]. The CYP system is a super-
phase II reaction. The latter are conjugation reactions which family of membrane-bound heme proteins that catalyze the
covalently link the drug or metabolite with a highly polar biotransformation of endogenous (i.e., steroids) and exogen-
molecule which renders the conjugate very water-soluble ous compounds [17,18]. CYPs are called mixed-function oxi-
and thereby excreted. Phase I and II reactions can occur dases or monooxygenases, because they insert one atom of
on the same molecule. Alternatively, drugs may undergo molecular oxygen into the substrate and one atom into water.
only phase I or only phase II reactions (the latter if a CYPs can also catalyze other reactions, such as reduction.
functional group is already present). Drugs may be elimin- The mixed-function oxidase system involves several
ated unchanged, or as their phase I metabolites, or as phase II enzymes in addition to CYP, including the requisite participa-
conjugates. tion of the flavoprotein NADPH-cytochrome P450 reductase,
Phase I reactions include oxidation, reduction, dehydrogen- as well as NADPH-cytochrome b5 reductase and cytochrome b5.
ation, and hydrolysis. They are typically (except hydrolysis) cata- The typical oxidation reaction generally involves an initial
lyzed by cytochrome P450 (CYP; see below). Most are carbon hydroxylation, with NADPH providing two electrons to reduce
74
one atom of molecular oxygen to water and insert the other into Regulatory agencies now require this of all drugs in develop-
the substrate. The overall scheme can be represented as: ment. For each CYP isoform, prototypic selective substrates
and inhibitors have been identified, and are used for reaction
RH þ O2 þNADPH þ Hþ
! ROH þ H2 O þ NADP
þ
phenotyping [25]. This is accomplished in vitro by identifying
where RH is the substrate and ROH is the oxidized metabolite. (1) which individual cDNA-expressed CYP isoforms metabol-
In rare cases, NADPH-cytochrome P450 reductase itself can ize the drug, (2) which isoform-selective chemical inhibitors or
catalyze drug metabolism, such as nitro reduction or quinone antibodies inhibit metabolism of the drug by human liver
reduction. microsomes, and (3) correlations between the metabolism of
More than 50 human P450s have been identified, although a candidate drug with either the protein content or catalytic
only a small fraction are responsible for the majority of drug activity of specific CYP isoforms in microsomes from a popu-
metabolism (Fig. 6.2) [1–3]. lation of human livers.
The individual CYPs evolved from a common ancestor The actual contribution of any individual CYP isoform
protein, and are classified according to their sequence evolu- to overall in-vitro microsomal metabolism will depend on
tion [1,13]. CYPs that share > 40% sequence homology are the in-vitro intrinsic clearance (Vmax/Km, as defined in
grouped in a family (designated by an Arabic number, e.g., Chapter 5) by that specific isoform, the relative content of
CYP2), those with > 55% homology are in a subfamily the isoform in the liver (or other organ), and the substrate
(designated by a letter, e.g., CYP2A), and individual CYPs concentration. Reaction phenotyping in vitro is optimally
are identified by a third number (e.g., CYP2A6). The major- evaluated at therapeutic drug concentrations. When reac-
ity of drugs in humans are metabolized by CYPs 1, 2, and 3 tions are performed at high substrate concentrations, the
(particularly CYPs 2C, 2D6, and 3A). CYPs are predomin- results must be interpreted cautiously. It is not uncommon
antly “microsomal” enzymes (as are glucuronosyltransferase for more than one CYP to catalyze a metabolic pathway. The
and glutathione transferase). Microsomes are not a physiolo- relative importance of each CYP to a specific pathway of
gic organelle, but rather correspond to the smooth endoplas- metabolism depends on the in-vitro intrinsic clearance and
mic reticulum. the relative isoform content in organs.
CYPs can have numerous genetic variants; indeed, there Identification of a predominant CYP isoform in vivo is
are several highly polymorphic CYPs. Allelic CYP variants are accomplished using analogous methods [26,27]. CYP isoform-
designated by an asterisk and number (e.g., CYP3A5*3, where selective inducers (drugs which increase the enzyme tissue
the “wild-type” is always designated CYP3A5*1) [1,13]. Since content and/or activity) and inhibitors (often the same ones
identification of new genetic variants is ongoing, a website used in vitro) can be used to evaluate their effect on metabol-
(www.cypalleles.ki.se) is updated regularly with new variants ism of the candidate drug. In a population of subjects, one can
and their frequencies. also correlate the metabolism of a candidate substrate with the
CYP isoforms can exhibit varying degrees of substrate subjects’ CYP phenotype or genotype.
specificity. Some, such as CYP2E1, have a relatively small The expression of various CYPs in human liver, and the
and restrictive active site and accept only structurally similar fraction of common clinically used drugs which they metabolize,
substrates. Others, such as CYP3A, have a very open and are shown in Fig. 6.2. Five CYPs (1A2, 2C9, 2C19, 2D6, and 3A4)
accommodating active site (indeed at least two active sites) catalyze ~ 95% of CYP-mediated drug biotransformation (~ 75%
[19]. They are called promiscuous because they metabolize a of all drug metabolism). From the perspective of anesthesiology,
large number of structurally diverse substrates. Similarly, sub- the most important are CYPs 2B6, 2D6, 2E1, and 3A.
strates can exhibit a low degree of P450 isoform selectivity
(antipyrine is metabolized by CYPs 1A2, 2A6, 2C9, 2C19, 2D6, CYP3A
2E1, and 3A) [20] or a very high degree of isoform selectivity The CYP3A subfamily is the most significant group of bio-
(meperidine and nifedipine are metabolized predominantly by transformation enzymes in clinical medicine, responsible for
CYP3A4, with little or no metabolism by the highly similar metabolizing over half of all drugs [28–30]. The important
CYP3A5) [21]. Isoform selectivity can also exhibit an unusual CYP3A isoforms are CYP3A4, the polymorphically expressed
oxygen dependence, as exemplified with halothane, which CYP3A5, and the fetal form CYP3A7. CYP3A enzymes in
undergoes oxidation by CYPs 2E1 and 2A6, and reduction by toto are the predominant CYP in human liver and intestine.
2A6 and 3A4 [22]. CYPs can also exhibit regioselectivity, CYP3A enzymes exhibit very broad substrate specificity
specifically oxidizing only one portion of a molecule. For (Table 6.1), with drugs ranging in size from halothane (a
example, CYP1A2 catalyzes ropivacaine 3-hydroxylation, while two-carbon alkane, mw 197) to cyclosporine (mw 1206).
CYP3A4 catalyzes 4-hydroxylation, 2-methyl-hydroxylation, CYP3As also catalyze a wide variety of oxidative and reduc-
and N-dealkylation [23]. tive biotransformation reactions.
Identification of the major CYP isoform(s) (or other CYP3A4 is the most quantitatively abundant CYP in
enzymes) responsible for metabolizing drugs is termed reac- human liver, accounting for, on average, 30% of total hep-
tion phenotyping, and is done both in vitro and in vivo [24]. atic CYP and as much as 60% in some livers. It is also the
75
Table 6.1. Representative human CYP3A substrates, inhibitors, and content and activity several-fold. Prototype inhibitors are
inducers
the macrolide antibiotic troleandomycin, the antifungal
Substrates ketoconazole, and the protease inhibitor ritonavir, although
other drugs in the same class (protease inhibitors) also
Opioids alfentanil,a fentanyl, sufentanil,
methadone, l-a-acetylmethadol
inhibit CYP3A4. Drugs which are CYP3A4 substrates can
(LAAM), buprenorphine, codeine, competitively inhibit the metabolism of other CYP3A4
dextromethorphan drugs. There is wide interindividual variability in CYP3A4
activity, but no clinically significant genetic polymorphisms
Benzodiazepines midazolam,a triazolam, diazepam,
or ethnic differences in activity have been found to date.
alprazolam, temazepam
CYP3A5 is similar to CYP3A4 and metabolizes many but
Local anesthetics lidocaine, bupivacaine, ropivacaine, not all CYP3A4 substrates, usually with diminished activity
cocaine [31]. CYP3A5 is polymorphically expressed, both in liver
Calcium antagonists verapamil, diltiazem, nifedipine, and intestine, in 5–15% of Caucasians, ~ 40% of Chinese,
nicardipine, nimodipine, felodipine, and > 50% of African-Americans. When present, it may account
amlodipine for more than half of the hepatic and an average of 25% of the
Immunosuppressants cyclosporine, tacrolimus intestinal CYP3A in some individuals [3]. CYPs 3A4 and 3A5 are
induced and inhibited by many of the same drugs. Individuals
Miscellaneous erythromycin,a tamoxifen, paclitaxel,
expressing CYP3A5 along with 3A4 may have greater metabol-
ondansetron, granisetron, lovastatin,
simvastatin, atorvastatin, cortisol,
ism of some (alprazolam, tacrolimus) but not other (midazolam,
terfenadine, astemizole, quinidine, alfentanil, verapamil) CYP3A drugs, for reasons not yet known
cisapride, lansoprazole, imipramine, [32]. CYP3A5 is the major CYP in human kidney [33]. Unlike the
amitriptyline, cyclophosphamide, liver, in which 3A4 is ubiquitous and 3A5 is sometimes
dapsone, amiodarone, testosterone expressed, in the kidney CYP3A5 is ubiquitous and 3A4 is
Inhibitorsb
expressed in only about 25% of subjects. Renal CYP3A may have
a role in drug metabolism.
Macrolides troleandomycin,a erythromycin, CYP3A7 is also similar to CYP3A4. It is expressed exclu-
clarithromycin sively in fetal liver, comprising 50% of total CYP. The metabolic
Antifungals ketoconazole,a miconazole, capabilities of CYP3A7 are similar to those of 3A4 and 3A5.
itraconazole, fluconazole, clotrimazole
HIV drugs indinavir, nelfinavir, ritonavir, CYP2D
saquinavir, amprenavir, nefazodone, CYP2D6, although accounting for only 2–5% of total human
delavirdine hepatic CYP protein, nonetheless metabolizes 20–25% of all
Miscellaneous grapefruit juice, 3A4 substrates
drugs and is one of the most important human CYPs [13,34–36].
It is also of considerable historical significance, being the first
Inducers identified CYP genetic polymorphism (named the “debriso-
rifampicin,a phenobarbital, phenytoin, quine/sparteine polymorphism,” after the two drugs whose
carbamazepine, dexamethasone, metabolism was bimodally distributed). The prototype CYP2D6
nelfinavir, efavirenz substrate probe is dextromethorphan O-demethylation, and
a
The most widely used human in-vivo probes (selective substrates and quinidine the standard inhibitor. CYP2D6 is not inducible by
inhibitors). drugs or hormones. A representative sample of CYP2D6 sub-
b
Many inhibitors and inducers are also substrates. strates and inhibitors is listed in Table 6.2. The list is notable
for a group of opioids which undergo both CYP2D6-mediated
O-demethylation and CYP3A4-mediated N-demethylation
predominant CYP in human intestine (Fig. 6.2B). Of (Fig. 6.4). Most pertinent is codeine, now known to be a
importance in anesthesiology, CYP3A4 metabolizes all of prodrug requiring metabolic activation to morphine [36].
the fentanyl-series synthetic opioids except remifentanil, The genetic and drug interaction implications of codeine
most benzodiazepines, and local anesthetics. Prototype metabolism are discussed below.
CYP3A4 substrates include midazolam and alfentanil. The CYP2D6 polymorphism is an autosomal recessive
CYP3A4 activity is remarkably susceptible to induction trait. More than 50 variant CYP2D6 alleles have been identi-
and inhibition, which alter the metabolism and clearance fied, which typically result in absent or catalytically deficient
of CYP3A substrates, often with profound clinical conse- CYP2D6 protein. Populations comprise efficient or extensive
quence (Table 6.1). The prototype inducer is rifampicin, metabolizers (EM, wild-type, homozygotes with normal CYP
but barbiturates, phenytoin, carbamazepine, glucocorticoids, activity), intermediate metabolizers (IM, heterozygotes with
and herbals such as St. John’s wort also increase CYP3A4 reduced CYP activity), poor metabolizers (PM, homozygotes
76
with absent activity), and ultrarapid metabolizers (UM, with of adverse effects among PM, and a higher incidence of
enhanced CYP activity due to gene duplication, up to 13 therapeutic failures among UM.
copies). The CYP2D6 genetic polymorphism exhibits ethnic
and racial as well as geographic diversity. The frequency dis- CYP2B
tribution in a typical European population is 70–80% EM, CYP2B6 is expressed primarily in liver, and also in intestine,
10–15% IM, 7–8% PM, and 2–10% UM. The PM frequency brain, kidney, and lung [37,38]. CYP2B6 was initially con-
is 7–8% in Caucasians, 2% in African-Americans, and < 1% sidered to be a minor enzyme, expressed in only some individ-
in Asians, and the UM frequency is 30% in Ethiopians, 10% uals and in low levels, and not important in human drug
in Spanish and Italians, 1–2% in northern Europeans, and < biotransformation. This was incorrect, however, and it is
1% in Asians. Table 6.3 lists geographic variability in now known that CYP2B6 is expressed in greater amounts
CYP2D6 phenotypes. For drugs which are inactivated (up to 6% of total CYP), in all individuals, metabolizes numer-
by metabolism via CYP2D6, there is a higher incidence ous drugs (~ 8% of total), and is clinically important [39]. The
prototype probe for human CYP2B6 is bupropion hydroxyla-
Table 6.2. Representative human CYP2D6 substrates and inhibitors tion and the inhibitor is clopidogrel. CYP2B6 is the primary
enzyme catalyzing propofol hydroxylation, and N-demethylation
Substrates
of methadone, meperidine, and both (R)- and (S)-ketamine
Opioids codeine, dextromethorphan,a [40–42]. 2B6 also metabolizes benzodiazepines (diazepam, tema-
dihydrocodeine, hydrocodone, oxycodone, zepam, midazolam) and other drugs such as verapamil, lido-
tramadol caine, and clopidogrel. Many drugs previously considered to
Antipsychotics haloperidol, perphenazine, risperidone, be metabolized predominantly by CYP3A are now known to
thioridazine, chlorpromazine be metabolized and cleared by both CYP2B and CYP3A, and
TCAs amitriptyline, clomipramine, desipramine,
sometimes only by CYP2B. For example, methadone clearance
imipramine, nortriptyline, clozapine, was formerly thought to be dependent on CYP3A, and the
maprotiline, trazodone drug label warns against CYP3A drug interactions. Nonethe-
less, it is now clear that while CYP3A does metabolize metha-
Antiarrhythmics encainide, flecanide, mexilitine,
done in vitro, it has little or no role in clinical methadone
procainamide, sparteine
metabolism and clearance [42,43]. Rather, CYP2B6 is the
β-blockers alprenolol, bufurolol, labetolol, metoprolol, primary determinant of methadone metabolism and clear-
propranolol, timolol, carvedilol ance, which is susceptible to CYP2B6 drug interactions [42–
SSRIs fluoxetine, fluvoxamine, paroxetine, 44]. Both CYP2B6 and CYP3A4 are highly inducible, and by
sertraline, citalopram, venlafaxine the same drugs (such as rifampicin and anticonvulsants), and
Miscellaneous debrisoquine, selegiline, tamoxifen, thus the potential for drug interactions with these 2B/3A
dolasetron, ondansetron, tropisetron substrates is considerable. CYP2B6 is highly polymorphic,
with a frequent (> 50% of African-Americans) allele resulting
Inhibitors
in enzyme with reduced activity (CYP2B6*6). Thus both
quinidine,a cimetidine, haloperidol, SSRIs genetic variability and susceptibility to induction/inhibition
a
The most widely used human in-vivo probes (selective substrates and account for the > 100-fold interindividual variability in
inhibitors). CYP2B6 activity.
dextromethorphan * ** dextrorphan ** Figure 6.4. Role of CYP2D6 and CYP3A4 in the

codeine * ** morphine bioactivation and inactivation of oral opioids. Path-
dihydrocodeine * O-demethylation dihydromorphine ways known to be metabolized by CYP2D6 and
hydrocodone * CYP2D6 hydromorphone CYP3A4 are indicated by * and **, respectively.
oxycodone * oxymorphone
tramadol * O-desmethyltramadol
N-demethylation N-demethylation
CYP3A CYP3A
3-methoxymorphinan * 3-hydroxymorphinan
norcodeine normorphine
nordihydrocodeine O-demethylation
norhydrocodone
CYP2D6
noroxycodone
N-desmethyltramadol N,O-didesmethyltramadol
77
Table 6.3. Geographic variability in the frequency of CYP2D6 phenotypes
Region Poor Intermediate Extensive Ultrarapid

metabolizers metabolizers metabolizers metabolizers
America 0 0 93 9
Sub-Saharan 2 16 77 5
Africa
North Africa 0 10 50 40
Middle East 1 10 76 12
Europe 8 5 84 2
Central/South 1 6 91 1
Asia
East Asia 0 30 68 1
Oceana 0 0 75 25
Frequencies are based on data in Ingelman-Sundberg et al. [13].
Other CYPs importance, because it metabolizes numerous small molecules,

CYP1A2 is expressed almost exclusively in the liver, while halogenated hydrocarbons and solvents, and it is of paramount
CYP1A1 is almost exclusively found extrahepatically, particu- importance in anesthesia because it metabolizes all the volatile
larly in the lung [45]. CYP1As are inducible by cigarette anesthetics [51]. The prototypic substrate probe is chlorzoxa-
smoke, charbroiled foods, and polycyclic aromatic hydrocar- zone and the standard inhibitor is disulfiram (and in vitro its
bons. Overall, CYP1A2 metabolizes a small fraction of thera- primary metabolite diethyldithiocarbamate). CYP2E1 is highly
peutic drugs, but the list includes caffeine, phenacetin, and inducible, both pathophysiologically (obesity, diabetes) and by
ropivacaine [23]. CYP1A1 metabolizes polycyclic aromatic numerous chemicals. There are mutant CYP2E1 alleles, but
hydrocarbons. they appear to be of little clinical significance. CYP2E1 is the
CYP2A6 is expressed mainly in the liver, and also in the primary enzyme oxidizing the volatile anesthetics halothane,
respiratory tract [46]. CYP2A metabolizes a small number of enflurane, isoflurane, sevoflurane, desflurane (most likely), and
drugs (notably methoxyflurane and halothane) and a large methoxyflurane, although the last is metabolized by several
number of environmental toxins, carcinogens, and nicotine. CYPs. CYP2E1 is responsible for the oxidative metabolic acti-
It catalyzes both the aerobic oxidation and anaerobic reduction vation of halothane, which results in halothane hepatitis
of halothane, and, although it is the minor CYP isoform [22,52]. In humans, CYP2E1 is expressed primarily in the liver,
responsible for human halothane oxidation, may nonetheless but not in the kidney. This may explain in part why, despite
play a role in immune-based halothane hepatitis. There is wide hepatic metabolism and defluorination of both methoxyflur-
interindividual variability in CYP2A6 activity. ane and sevoflurane, methoxyflurane (metabolized by many
CYP2C is a major class, containing CYPs 2C8, 2C9, 2C18, CYPs) is metabolized in the kidney and is nephrotoxic, while
and 2C19, together accounting for about a fourth of total sevoflurane (metabolized only by CYP2E1) is not metabolized in
hepatic CYP and metabolizing approximately 15–20% of all the kidney and is not nephrotoxic [51]. In contrast to the situ-
therapeutic drugs [47]. CYP2Cs are of little relevance in anes- ation in humans, CYP2E1 is expressed in rat kidney. This species
thesia, except that they metabolize barbiturates and diazepam. difference has implications for interpreting animal models of
A CYP2C19 polymorphism accounts for inter-racial differ- CYP2E1-mediated anesthetic metabolism and toxicity [53].
ences in the clinical disposition and dose requirements for
diazepam, particularly PM homozygotes. For perspective, the
major isoform determining the elimination and clinical effects Non-P450 enzymes
of warfarin is CYP2C9, which has highly significant genetic Esterases
polymorphisms that affect clinical outcome and toxicity. In the Ester/amide hydrolysis is a ubiquitous reaction catalyzed by a
future, patients may undergo genetic testing to determine diverse array of enzymes in blood and tissue. Two major
warfarin dosing [48]. enzyme families catalyzing these reactions are carboxyles-
CYP2E1 comprises approximately 6% of total hepatic terases and cholinesterases, both of which are critically import-
P450, and metabolizes few drugs (notable exceptions being ant in anesthetic pharmacology.
paracetamol [acetaminophen] and ethanol) [49,50]. Neverthe- Carboxylesterases are predominantly microsomal enzymes
less, it is of considerable toxicological and carcinogenic with wide tissue distribution [54,55]. Human carboxylesterase
78
expression is highest in the liver, and also occurs in the gastro- Remifentanil is hydrolyzed by nonspecific esterases in plasma
intestinal tract, brain, and possibly blood. They have a very and (more so) in tissue, but not by plasma cholinesterase [58].
nonselective substrate specificity and also hydrolyze amides, Hence remifentanil elimination is not altered by pseudocholi-
thereby converting esters and amides to more water-soluble nesterase deficiency or by hepatic insufficiency [59]. In con-
acids, alcohols, and amines that are subsequently eliminated. trast, and unlike most ester drugs, esmolol metabolism in
Microsomal carboxylesterases are inducible by many of the humans is catalyzed exclusively by esterases in erythrocytes
compounds which induce microsomal CYP. Two broad-sub- rather than in plasma.
strate human liver microsomal carboxylesterases have been
Others
isolated (hCE-1 and -2). For example, hCE-1 catalyzes the metab-
Numerous other enzymes act on xenobiotics, but are quanti-
olism of cocaine to benzoylecgonine, meperidine to meperidinic
tatively less important than those above with respect to the
acid (the major metabolite), and heroin (3,6-diacetylmorphine)
metabolism of therapeutic drugs. These include monoamine
to 6-monoacetylmorphine, the active metabolite. hCE-2 also
oxidase. flavin monooxygenase, aldehyde oxidase, alcohol
hydrolyzes heroin both to 6-monoacetylmorphine and then to
and aldehyde dehydrogenases, the oxidoreductases xanthine
morphine.
oxidase-xanthine dehydrogenase, and epoxide hydrolases.
Human cholinesterases include acetylcholinesterase
(AChE) and plasma cholinesterase (also known as serum cho- Phase II enzymes
linesterase, pseudocholinesterase, butyrylcholinesterase, and There are several enzyme families including methyl- and sul-
nonspecific cholinesterase) [56,57]. The major function of fotransferases, acetyl- and acyltransferases, glucuronosyltrans-
AChE is to hydrolyze acetylcholine at the neuromuscular junc- ferases, and glutathione transferases which directly conjugate
tion, thereby terminating synaptic transmission. Two other drugs, or conjugate their oxidative metabolites.
AChE forms are located in erythrocytes and the brain.
Plasma cholinesterase is widely distributed in blood, liver, Glucuronosyltransferase
and other tissues, and has an unknown physiologic role but Uridine diphosphate glucuronosyltransferases (UGTs) are a
great relevance to drug metabolism. It contains two active sites, family of microsomal enzymes that add glucuronic acid to a
the anionic site and the esteratic (catalytic) site at which ester variety of lipophilic compounds containing phenolic, alcohol,
hydrolysis actually occurs. Activity is mildly to moderately amine, carboxyl, or sulfhydryl groups [60]. UGTs are
decreased by pregnancy, liver disease, renal failure, and car- expressed predominantly in the liver. Glucuronides are more
diopulmonary bypass (from hemodilution), and markedly water-soluble than their parent compounds, circulate freely in
inhibited by ecothiopate, organophosphate pesticides, and plasma, and are rapidly excreted in bile or urine (depending on
reversible inhibitors of AChE (neostigmine, edrophonium, size). Glucuronides may be more or less pharmacologically
physostigmine, pyridostigmine). Plasma cholinesterase was active than their parent drugs. Since the intestine contains
one of the first enzymes for which pharmacogenetic variation significant amounts of β-glucuronidase, which hydrolyzes glu-
was elucidated, based on heritable interindividual variability in curonides back to their parent compounds, the free com-
the response to succinylcholine (see Chapter 10) [56]. pounds can be intestinally reabsorbed and transported to the
The prototype substrate for plasma cholinesterase is succi- liver to undergo re-conjugation and re-excretion; this is
nylcholine, which is successively hydrolyzed to succinylmono- referred to as enterohepatic recirculation.
choline and to succinic acid. Hydrolysis is rapid, with 90% of a There are 15 human UGTs, broadly classified into the
dose metabolized within one minute, and thereby presystemic UGT1 (phenol/bilirubin) and UGT2 (steroid/bile) families.
clearance is substantial and robust (a 70% reduction in enzyme UGT1As glucuronidate endogenous compounds and a consid-
activity only moderately prolongs neuromuscular blockade). erable number of drugs (phenols, amines, anthraquinones,
Mivacurium is also hydrolyzed by plasma cholinesterase, flavones). UGT2A and 2B enzymes glucuronidate bile acids,
at a rate 70–90% of that of succinylcholine. Patients with steroids, and retinoids and a few drugs. UGT2B7 has the
cholinesterase variants respond similarly to mivacurium broadest substrate specificity among 2B isoforms. Glucuroni-
and succinylcholine. The ester local anesthetics cocaine, pro- dation is inducible by barbiturates, antiepileptics, and rifampi-
caine, and chloroprocaine are metabolized by plasma cholines- cin, and inhibited by probenecid.
terase. Heroin undergoes extensive deacetylation in blood to Glucuronidation is an important biotransformation path-
6-monoacetylmorphine, and further hydrolysis to morphine. way for certain drugs in anesthesia. Glucuronidation by liver
The former reaction is catalyzed rapidly by plasma cholines- and kidney UGT1A9 is the major route of systemic propofol
terase, and more slowly by erythrocyte AChE, although the elimination [61]. UGT2B7 glucuronidates a number of opioids
latter reaction accounts for the majority of hydrolysis in vivo, such as morphine (both the 3- and 6- positions), codeine,
and only erythrocyte AChE can convert 6-monoacetylmor- naloxone, nalorphine, buprenorphine, oxymorphone, and
phine to morphine. hydromorphone [62]. Morphine 6-glucuronidation is particu-
Other drugs, including remifentanil and esmolol, also larly important, since this metabolite is more potent than its
undergo extensive biotransformation and inactivation. parent drug, can play a significant role in analgesia, and the
79
finding of UGT2B7 in human brain suggests that in-situ for- or steroid functionalities. Sulfation is an important pathway in
mation of morphine-6-glucuronide may play a role in anal- neonates for elimination of paracetamol and morphine.
gesia [63,64]. The glucuronide of 1-hydroxymidazolam is
pharmacologically active, circulates in high concentrations in
plasma, is renally excreted, and is thought to underlie the
Extrahepatic metabolism
prolonged effects of midazolam in patients with renal insuffi-
ciency when used for ICU sedation.
Intestine
Almost all biotransformation enzymes expressed in the liver
are also present in the intestine, albeit at lower content
Glutathione-S-transferase
[7,8]. Principle enzymes include the CYPs, esterases, alcohol
Glutathione-S-transferases (GST) catalyze the reaction of the
dehydrogenase, glucuronosyltransferases, sulfotransferases,
tripeptide glutathione (gly-cys-glu) with chemically reactive
N-acetyl-transferase, and glutathione transferases. Unlike the
drugs, metabolites, and environmental toxins [65]. GSTs are
liver, which has generally uniform regional distribution of
primarily a defensive system for detoxification and protection
biotransformation activity, many of the enzymes (especially
against oxidative stress, and hence are abundantly and ubiqui-
CYPs) are nonuniformly distributed in the intestine, with
tously expressed in most tissues. There are many cytosolic and
decreasing content from duodenum to ileum (75% of CYP3A
a few membrane-bound microsomal GSTs. The human soluble
is in the duodenum and jejunum), and a preferential expres-
cytosolic GSTs are largely responsible for conjugating toxins
sion at the apical portion of the intestinal villus. CYP3A (3A4,
and drugs.
and in some persons 3A5) is the predominant CYP, account-
Conjugation to glutathione generally renders the resulting
ing for most (> 70%) of total intestinal CYP (Fig. 6.2B) [3].
molecule more water-soluble, less chemically reactive, and
Total intestinal CYP3A4 content is less than that in liver, but
more rapidly eliminated. Nonetheless, for a small number of
higher than in other extrahepatic organs. Liver and gut
molecules such as halocarbons, glutathione conjugation con-
CYP3A4 are identical proteins, although they are independ-
stitutes a mechanism for bioactivation and toxification, specif-
ently regulated and not coordinately expressed. Their substrate
ically nephrotoxicity [66]. These conjugates are excreted in bile
profiles, activities, and responses to inducers and inhibitors are
and cleaved into corresponding cysteine conjugates, which
generally similar. One notable exception is that grapefruit juice
may be reabsorbed from the intestine. Cysteine conjugates
(except in massive doses) inhibits gut but not liver CYP3A.
may be N-acetylated, forming mercapturic acid conjugates,
Intestinal metabolism accounts for a significant portion of
which are nontoxic and excreted in urine. Circulating glu-
first-pass clearance of numerous orally administered CYP3A
tathione and cysteine conjugates and mercapturic acids can
substrates.
be actively taken up by renal proximal tubular cells, where they
may undergo bioactivation by the enzyme cysteine conjugate Kidney
β-lyase to highly reactive intermediates which cause proximal Human kidneys are fully capable of oxidizing and conjugating
tubular necrosis. This complex multi-organ, multi-enzyme drugs [71,72]. They express P450, GSTs, glutathione peroxid-
pathway is often referred to as the “β-lyase pathway” [66]. ase, and glutathione reductase, and flavin monooxygenases,
The haloalkene “compound A,” which results from sevoflurane esterases, glucuronyltransferases, N-acetyl-transferases, and
degradation by carbon dioxide absorbents, undergoes meta- cysteine conjugate β-lyase. Most of the extrahepatic glucuro-
bolism by this complex pathway, both in animals and in nidation in the body is thought to occur in the kidney. Indeed,
humans [67–70]. Compound-A nephrotoxicity in rats is attri- almost one-third of total-body propofol clearance occurs by
buted to glutathione- and β-lyase-dependent bioactivation. renal elimination, probably by intrarenal glucuronidation
The absence of human compound-A toxicity has been ascribed [73,74]. Total human kidney CYP content is approximately
to species differences in dose and relative metabolism by an order of magnitude less than in the liver. CYP3A enzymes
detoxication (mercapturate formation) versus toxification are the most abundant human renal CYPs, with 3A5 predom-
(β-lyase) pathways [70]. inant and both 3A4 and 3A5 variably expressed [33,75].
Although total renal microsomal CYP3A content (per mg
Others protein) is 2–3 orders of magnitude less than that of liver,
N-acetyl-transferase is a phase II enzyme which N-acetylates the specific content of CYP3A in proximal tubular cells (where
many amine-containing drugs (such as isonizaid and procai- CYPs are exclusively located) approximates that in hepato-
namide). Genetic polymorphism in N-acetyl-transferase segre- cytes. Renal CYP3As are fully competent to metabolize hepatic
gates populations into fast and slow acetylators, which may CYP3A substrates, and are thought to contribute significantly
influence therapeutic response and toxicity of some drugs. to the metabolism and/or clearance of drugs such as cyclo-
This pathway is of little importance to anesthetic drugs. Sulfo- sporine and methoxyflurane [76,77].
transferases, which are cytosolic, catalyze the transfer of a Human and rat kidneys differ markedly in their expres-
sulfate group to numerous endogenous and a small number sion of P450s and GSTs. Human kidneys express mainly
of exogenous compounds containing amine, phenol, alcohol, CYPs 3A and 4A [72,78]. In contrast, rat kidneys express a
80
considerable number of CYP isoforms [79]. An important produced by oxidation and conjugation do not readily cross
difference is the absence of CYP2E1 in human kidneys, par- the placenta back to the mother, thereby prolonging fetal
ticularly in comparison to human liver, where it constitutes exposure.
about 7% of total P450, and in rat kidneys, where it is highly Information on the individual drug-metabolizing enzymes
expressed. This is important because CYP2E1 is the major in pediatrics and the developmental aspects of biotransforma-
isoform responsible for the metabolism of most volatile anes- tion has grown exponentially in the past decade, and a detailed
thetics. The ability of human kidneys to metabolize methoxy- presentation is beyond this chapter, but generalities are addres-
flurane but not sevoflurane, explained by the metabolism of sable [83,84]. One group of enzymes (typified by CYP3A7,
the former by several P450s (including renal CYP3A) but the flavin monooxygenase, and sulfotransferases) have their
latter only by CYP2E1 (which is not present in human highest expression in the first trimester, remain at high con-
kidneys), is thought potentially to underlie the nephrotoxicity centrations or decrease during gestation, and are lower or
of methoxyflurane but not sevoflurane in humans, despite silenced by age 2. Another group (CYP3A5, CYP2C19, certain
their similar hepatic metabolism [77]. sulfotransferases) has relatively constant expression through
gestation, and CYP2C19 increases within the first year. Most
Other enzymes (CYPs 2A2, 2C9, 2D6, 2E1, 3A4, aldehyde dehydro-
Human brain is known to express P450s from all three
genase, and certain sulfotransferases) are missing or expressed
major families, although there are regioselective and isoform-
minimally in the fetus, with onset of expression often in the
selective differences in expression [80]. Cerebral P450 activity
second or third trimester, with substantial increases in expres-
is low, does not contribute to systemic drug elimination, but
sion in the first 1–2 years after birth. Increases in CYP during
may contribute to the blood–brain barrier and biosynthesis of
the neonatal period (< 4 weeks) are attributable primarily to
signaling molecules, and a few studies have shown the ability
CYP2C isoforms.
of human brain to metabolize psychotropic drugs.
CYP3A isoforms undergo the greatest and most complex
The lung is a major target organ for inhaled therapeutic
pattern of maturation, termed a “developmental switch” [84].
drugs, the obvious site of inhaled anesthetics delivery, and
CYP3A7 is the major isoform present in human embryonic,
nasal and inhaled drug delivery are an increasingly pursued
fetal, and newborn liver (Fig. 6.5A) [86]. It is expressed most
alternative for systemic drug administration. The major phase I
abundantly in gestation and declines rapidly after birth to
and II enzymes are expressed in human lung, and may partici-
less than 10% of newborn levels by 3–12 months. Fetal
pate in pulmonary first-pass metabolism, elimination, and tox-
CYP3A4 expression is minimal, but it rises immediately
ification [72,81].
after birth, concomitant with the decline in CYP3A7.
CYP3A4 activity reaches 30–50% of adult levels in the first
Biotransformation and age 2–5 years (Fig. 6.5B) [87]. CYP3A7 is also expressed in the
placenta and pregnant endometrium. Although CYP3A7 has
Pediatrics high sequence similarity to CYP3A4, and metabolizes several
Drug disposition, dosing, response, and adverse effects are 3A4 substrates, activity towards most substrates and some
substantially different in children and adults [82], with differ- hormones is considerably less than that of CYP3A4.
ences in biotransformation, and consequently pharmacoki- Morphine biotransformation illustrates important develop-
netics, a major reason [83,84]. The fetus is fully competent to mental differences in phase II metabolism, such as glucuroni-
metabolize hormones and drugs, and the liver is the main site dation and sulfation [83]. Fetal and neonatal hepatic
of fetal biotransformation, catalyzing both phase I and phase II glucuronidation is immature, < 10–30% of adult activity, and
reactions. There are significant age-dependent differences does not mature for several years into childhood. Morphine
in biotransformation, with the greatest changes occurring glucuronidation and clearance increase with both gestational
between birth and age 2 for phase I enzymes, and birth and and postnatal age. In contrast, sulfotransferase activity is
adolescence for phase II pathways, with comparatively minimal mature at birth, and can compensate for impaired glucuroni-
changes in activity between childhood and adulthood [83]. dation. Morphine is preferentially sulfated in neonates, but
Fetal and neonatal biotransformation is less than in infants preferentially glucuronidated in adults.
and adults. Anesthetic drugs with reduced clearance or meta-
bolism in neonates include diazepam, midazolam, fentanyl, Pregnancy
morphine, paracetamol, and naloxone [85]. Total hepatic Fetal drug metabolism, described above, occurs within the
CYP concentration at birth is approximately half that of adults, greater context of pregnancy [88,89]. Pregnancy increases
and the individual CYP isoforms mature at different rates. maternal hepatic activity of CYPs 2A6, 2C9, 2D6 and 3A4,
Maturation of drug-metabolizing enzymes, rather than and UGTs 1A and 2B7, while CYPs 1A2 and 2C19 are
changes in hepatic size or blood flow, is considered to be the decreased, altering drug disposition. The placenta is relatively
major factor responsible for these changes. Fetal drug meta- devoid of phase I enzymes, but rich in phase II enzymes and
bolism is unique, because the more water-soluble metabolites drug transporters which affect fetal drug exposure.
81
A B
0.6
0.5
MDZ Clearance (L/kg/hr)

0.4
0.3
0.2
0.1
0.0
t
yr
yr
yr
k
k
ul
w
w
Ad
1
15
39
1
0–
1–
–3
–3
2–
>
24
26
A
G
A
A
G
G
Figure 6.5. Developmental aspects of CYP3A expression and activity. (A) Content of hepatic CYP3A4, CYP3A5, and CYP3A7 protein as a function of age. EGA,
estimated gestational age; PNA, postnatal age. Reproduced with permission from Stevens [86] (B) Clearance of the CYP3A4 probe midazolam (MDZ). GA, gestational
age. Redrawn with permission from de Wildt et al. [87].
Geriatrics Applied clearance concepts

Like many physiologic functions in geriatrics, clinical drug Understanding the influence of disease and drug interactions on
biotransformation represent the combined influence of normal hepatic drug elimination requires further explication of the basic
aging, disease, environment, and drug interactions [90–92]. concept of hepatic clearance (CLH), the product of hepatic blood
Hepatic size and liver blood flow decline with age, and clear- flow (QH) and hepatic extraction ratio (EH) of a drug (Eqs. 6.1,
ance of many drugs appears to decline in healthy aging in 6.5). Drugs can be categorized by the efficiency of their removal
parallel with reduced liver volume. Nonetheless, biotransfor- by the liver, as high- (EH > 0.7), intermediate- (0.3 < EH < 0.7),
mation in the aging liver does not decline similarly for all or low-extraction (EH < 0.3) drugs. For high-extraction drugs,
enzymes, pathways and drugs, and there is increased interin- QH << fu · CLint and therefore CLH approaches QH, because the
dividual variability with aging. In general, the activity of phase I efficiency of extraction is so great that QH is a more rate-
reactions declines with age, particularly esterases. Some, but not limiting factor than metabolism. The systemic clearance of
all, studies suggest decreased activity of hepatic CYP isoforms. high-extraction drugs is “flow-limited,” depends on QH, and
In contrast, phase II reactions are considered to be relatively will be sensitive to changes in QH but insensitive to changes in
unchanged. metabolism (CLint). High-extraction drugs have low oral
bioavailability because of extensive first-pass hepatic metabol-
ism. For low-extraction drugs, QH >> fu · CLint and therefore
Interindividual and intraindividual CLH approaches fu · CLint. Thus the systemic clearance of low-
variability in drug metabolism extraction drugs is “capacity-limited,” depends on CLint, and is
highly susceptible to even small changes in CLint. Low-extrac-
Variability is a significant clinical issue which can markedly tion drugs have a high oral bioavailability. The extraction ratios
affect drug disposition and response [93]. Variability can often of commonly used anesthetics are shown in Table 6.4.
result in > 100-fold ranges in drug exposure (area under the
concentration–time curve), potentially even rendering patients Drug interactions
nonresponsive to certain drugs or causing toxicity. Causes of Metabolic drug–drug and drug–diet interactions are a major
interindividual variability include genetics (sex, race, ethnicity, source of both inter- and intraindividual variability in drug
enzyme polymorphisms), age, environment (diet, smoking, disposition, clinical response, and toxicity [7,94–96]. Such
ethanol, solvent or other xenobiotic exposure), disease, and interactions are hepatic, intestinal, or both (Fig. 6.3), and occur
drug interactions. Many of the genetic causes of variability most with phase I reactions (specifically CYP). CYP induction
have been addressed above. (usually increased expression, although decreased degradation
82
can occur with CYP2E1) results in increased enzyme activ- of midazolam, and the greater effect after oral versus IV
ity. CYP inhibition can be noncompetitive or competitive. administration, is shown in Fig. 6.7 [97,99].
CYP inhibitors and inducers are classified as weak, moder- The role of biotransformation, pharmacogenetics, and drug
ate, or strong, corresponding to a 1.25-, 2-, or 5-fold change interactions in interindividual variability in drug disposition
in the plasma area under the concentration–time curve and response is illustrated by codeine, a prodrug requiring
(AUC), and corresponding to a 20–50%, 50–80%, or CYP2D6-mediated metabolic activation (O-demethylation)
> 80% change in clearance. Drug interactions are con- to the m-opioid agonist morphine, and further UGT2B7-
stantly being discovered, and review articles may not be as mediated metabolism to the agonist morphine-6-glucuronide
current as websites, such as one maintained particularly for [36]. CYP2D6-deficient individuals are poor metabolizers
this purpose [18]. (PMs) of codeine, with markedly diminished or absent mor-
The kinetic consequences of enzyme inhibition and induc- phine formation and minimal if any analgesia (Fig. 6.8A)
tion are dependent on the extraction ratio and route of [100]. Conversely, individuals with CYP2D6 gene duplication
administration of the drug [4]. For example, systemic clear- (ultrarapid metabolizers) have greater morphine formation,
ance of the low-extraction opioid alfentanil is exquisitely and may be predisposed to toxicity. Ethnic variations attribut-
sensitive to hepatic CYP3A induction and inhibition, while able to codeine biotransformation have also been observed.
that of the high-extraction opioids fentanyl and sufentanil is For example, Chinese subjects produced less morphine from
less affected (Fig. 6.6) [97,98]. For orally administered drugs, codeine, were less sensitive to the opioid effects of codeine, and
the changes in AUC with induction and inhibition will always might therefore experience reduced analgesia from codeine
be greater than those after IV administration, particularly for [101,102]. The metabolic drug interaction with the CYP2D6
intermediate- and high-extraction drugs. In addition, the inhibitor quinidine markedly diminishes codeine bioactiva-
differences in the percentage change in the AUC after oral tion and morphine formation (Fig. 6.8B) [103]. Interactions
versus IV administration are greater for high- than with low- at pathways other than bioactivation or inactivation can also
extraction drugs. The influence of CYP3A induction and have metabolic consequence. For example, rifampicin induc-
inhibition on the metabolic elimination and clinical sedation tion of CYP3A4 increased codeine N-demethylation (Fig. 6.4),
making less codeine available for O-demethylation, and
thereby decreasing the formation of morphine [104].
Table 6.4. Hepatic extraction of some commonly used drugs
Low extraction thiopental, diazepam, lorazepam, Pharmacogenetics

(EH < 0.3) triazolam, theophylline, alfentanil, It is clear from the preceding information that genetics can be
methadone a major contributor to interpatient variability in drug metab-
Intermediate methohexital, midazolam, vecuronium, olism and drug response, both therapeutic and toxic. Clinical
extraction rocuronium, ropivacaine, mepivacaine, tests for determining CYP polymorphisms are now techno-
hydromorphone logically available, and can be highly effective in individual-
izing drug selection and dosing, particularly of drugs with a
High extraction etomidate, propofol, ketamine,
narrow therapeutic index [105]. Nevertheless, their clinical
(EH > 0.7) bupivacaine, lidocaine, metoprolol,
propranolol, labetolol, fentanyl, sufentanil, implementation is limited and their practical utility is not yet
remifentanil, meperidine, morphine, clear [48,106]. It is likely that genetic testing will become more
naloxone ubiquitous, if not required by regulatory agencies, towards the
goal of “personalized medicine.” Likely candidates are warfarin
100 10 Figure 6.6. Influence of hepatic extraction ratio of

the consequence of a drug interaction. CYP3A activ-
ity and intrinsic clearance were reduced by adminis-
Plasma Alfentanil (ng/ml)
Plasma Fentanyl (ng/ml)
tering the CYP3A inhibitor troleandomycin prior to

10 IV injection of the opioids alfentanil (low-extraction)
1 or fentanyl (high-extraction). Alfentanil clearance
CYP3A inhibition was inhibited 88% (from 5.5
2.2 to 0.6
0.2 mL
CYP3A inhibition
kg–1 min–1) while fentanyl clearance was reduced by
1
only 40% (from 15.3
5.0 to 9.4
3.1 mL kg–1 min–1).
Redrawn with permission from Ibrahim et al. [98].
0.1
0.1
Control Control
0.01 0.01
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (hr) Time (hr)
83
A B C
100 30
50 Itraconazole
25
40
Midazolam (ng/ml)
Midazolam (ng/ml)
Drowsiness (mm)
10 20
Troleandomycin
30
15
Troleandomycin
Grapefruit Juice
10 20 Control
1
Grapefruit Juice
Control 5 10
Control
Rifampin Rifampin Rifampin
0.1 0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 1 2 3 4 5 6 7 8
Time (hr) Time (hr) Time (hr)
Figure 6.7. Influence of CYP3A drug interactions on midazolam disposition and clinical effects. (A and B) Effect of hepatic and intestinal CYP3A induction by rifampicin,
hepatic and intestinal CYP3A inhibition by troleandomycin, and selective intestinal CYP3A inhibition by grapefruit juice on plasma of midazolam concentrations after (A)
IV midazolam 1 mg and (B) oral midazolam 3 mg. Redrawn with permission from Kharasch et al. [97]. (C) Effect of hepatic and intestinal CYP3A induction by rifampicin,
and hepatic and intestinal CYP3A inhibition by itraconazole on sedation after 15 mg oral midazolam. Redrawn with permission from Backman et al. [99].
1000 Figure 6.8. Influence of CYP2D6 activity on

Reduction in VAS Pain Score (mm)
EM Control codeine metabolism and analgesia. (A) Pharmaco-

8 genetic effects. Shown are the median of the peak
PM Quinidine
changes in peak pain during a cold pressor test in
100 CYP2D6 extensive (EM) and poor (PM) metabolizers
Concentration (nM)
6 who received morphine or codeine. Morphine anal-

gesia was the same in EMs and PMs. Plasma codeine
concentrations were not different in PMs and EMs,
10 but morphine and morphine-6-glucuronide were
4
undetectable in plasma of PMs. Codeine reduced
pain only in the EMs. Redrawn with permission from
Poulsen et al. [100]. (B) Drug interaction effects.
2 1
Median plasma and cerebrospinal fluid (CSF) con-
centrations of codeine and morphine in 17 patients
2 h after 125 mg oral codeine without or with
0 0.1 CYP2D6 inhibition by pretreatment with 200 mg
morphine (20 mg) codeine (75 mg) Plasma CSF Plasma CSF oral quinidine. Codeine concentrations were not
Codeine Codeine Morphine Morphine different, but CYP2D6 inhibition reduced morphine
concentrations. Redrawn with permission from
Sindrup et al. [114].
therapy (CYP2C9) and antineoplastic drugs (CYP2D6 for tam- is diminished more than phase II conjugation activity (glucur-
oxifen therapy of breast cancer, thiopurine methyltransferase onidation) in mild–moderate cirrhosis because of greater sus-
for 6-mercaptopurine and azathioprine, and UGT1A1 for ceptibility to the relative hypoxemia in cirrhosis, but
irinotecan) [106]. glucuronidation is impaired in advanced disease. Worsening
liver disease (based on the Child–Pugh classification) is gener-
Biotransformation in disease ally associated with greater reduction in intrinsic clearance
Liver disease can markedly affect drug biotransformation, with than in hepatic blood flow. Evaluation of biotransformation
significant clinical consequences, including for anesthesia capabilities of orthotopic liver transplants, in comparison with
[107]. A discussion of hepatic disease and pharmacokinetics age-matched controls, found the clinical activities of CYPs
in general is found in other chapters. Impaired drug metabol- 2C19 and 2D6 lower, CYPs 1A2 and 3A4 unchanged, and
ism in chronic liver disease can result from reduced liver mass, CYP2E1 greater, measured one month after transplant [109].
reduced enzymatic activity in remaining hepatocytes, or The consequence of liver disease on hepatic drug clearance will
diminished hepatic blood flow. There is nonhomogeneous depend, as it does for drug interactions, on the extraction ratio
and variable reduction in the activity of various CYP isoforms of a drug, as well as on disease severity. Hepatic clearance of
with worsening liver disease, with the earliest and most pro- low-extraction drugs (e.g., alfentanil) is diminished even with
found reductions in the order CYP2C19 > 1A2 > 2D6 > 2E1, mild–moderate disease, while that of high-extraction drugs
with 3A4/5 also very significantly affected [108]. CYP activity (e.g., morphine, lidocaine) is relatively unchanged. More
84
severe liver disease, such as cirrhosis with alterations in QH In drug development, elucidation of biotransformation
and portosystemic shunting, will have a significant impact on pathways and mechanisms now occurs early in the develop-
the CLH of high-extraction drugs. ment timeline, and regulatory agencies now require consider-
Kidney disease reduces glomerular filtration rate and there- able information about drug metabolism and drug
fore the renal clearance of drugs which are eliminated entirely interactions. Information on the latter, which was traditionally
or partly by the kidney, with consequently altered pharmaco- gathered over long periods of clinical use via reports of adverse
kinetics. While it is well understood that such drugs require drug reactions, is now prospectively determined from in-vitro
dose adjustment in patients with acute or chronic renal failure, enzyme systems and clinical models of biotransformation. Far
it was widely assumed that drugs cleared by hepatic metabol- more is known about the metabolism of recently developed
ism and transport (nonrenal clearance) were unaffected by drugs than those developed decades ago.
renal disease. That notion has been refuted, and it is now clear Metabolism plays a prominent role in the disposition of
that renal failure affects intestinal absorption and first-pass numerous drugs used in anesthesia, including opioids (fenta-
metabolism, hepatic metabolism and clearance, and hepatic, nyl, alfentanil, sufentanil, remifentanil, morphine, codeine,
intestinal, and renal transport, with the clinical consequence of oxycodone, hydrocodone, hydromorphone, dextromethor-
altered nonrenal clearance (30–90% reduction) and bioavail- phan, meperidine, methadone), sedative-hypnotics (propofol,
ability (70–100% increase) [110,111]. Circulating uremic fospropofol, thiopental, methohexital), benzodiazepines (mid-
factors (some of which are dialyzable) are thought to cause azolam, triazolam, diazepam, alprazolam), local anesthetics
chronic inflammation and cytokine upregulation, leading to (lidocaine, bupivacaine, ropivacaine, procaine, chloroprocaine,
downregulation of hepatic and intestinal CYP, phase II conju- cocaine), neuromuscular blockers (succinylcholine, rocuro-
gation enzymes, and transporters. For example, morphine glu- nium, vecuronium, pancuronium, mivacurium, (cis-)atracur-
curonidation is significantly impaired in chronic renal failure, ium), and volatile anesthetics (particularly the more soluble
but midazolam clearance (reflecting hepatic CYP3A activity) is ones). Metabolism is central to the mechanism by which
unaffected. Patients with renal insufficiency should not be methoxyflurane caused renal failure, halothane caused hepa-
assumed to have normal drug biotransformation and clearance. titis, and meperidine can cause seizures.
Systemic diseases such as infection and inflammation Drug metabolism can result in bioactivation of an inactive
diminish the expression and activity of CYPs and other drug- prodrug, formation of an active or inactive metabolite, or
metabolizing enzymes, with consequently altered drug clear- occasionally a toxic metabolite. Phase I metabolism chemically
ance [112,113]. This is thought to be secondary to increased modifies the drug structure, and phase II metabolism adds an
cytokine production and suppression of transcription. Hepatic endogenous molecule to the drug or metabolite to render it
and intestinal drug metabolism can be suppressed by both even more water-soluble for elimination. The cytochrome
acute and chronic inflammation. It appears that CYPs can be P450 (CYP) enzyme system is the most important for metab-
regulated by multiple cytokines, that the CYP isoforms regu- olizing therapeutic drugs, and the CYPs most relevant to
lated by individual cytokines differ, and thus the drugs whose anesthesiology are CYP2B6, CYP2D6, CYP2E1, and CYP3A.
disposition is altered may vary with the acute inflammatory Esterases are also important in clinical anesthesia. Drug
stimulus, chronic disease, or the immunomodulatory drug. metabolism has been deliberately exploited in anesthetic devel-
opment to target routes or sites of metabolism, develop pro-
Summary drugs, and accelerate or retard rates of drug inactivation.
Drug metabolism is also a major determinant of interindi-
Biotransformation, or drug metabolism, is a major determin- vidual variability in drug effect, due to pharmacogenetic dif-
ant of drug bioavailability, clearance, clinical effect, and tox- ferences and drug interactions. Indeed, pharmacogenetics as a
icity. This is a complex and diverse field which has undergone discipline has its roots in drugs used in anesthesia. Interindi-
explosive growth in the last two decades owing to the applica- vidual variability in drug metabolism, potentially resulting in
tion of molecular biology and genetic techniques to a tradition- > 100-fold ranges in drug exposure, is a significant clinical
ally more chemically oriented discipline. The entire process of issue which can markedly affect drug pharmacokinetics, clin-
drug disposition (pharmacokinetics) encompasses absorption, ical response, and toxicity. Causes of variability include genet-
distribution, metabolism, and elimination (“ADME”), and ics (sex, race, ethnicity, and genetic polymorphisms in enzyme
sometimes includes toxicity (“ADMET”), because toxicity often activity), age, environment (diet, smoking, chemical exposure),
relates to biotransformation. Drug metabolism is not an isol- disease, and drug interactions. Biotransformation activity at
ated pharmacokinetic phenomenon. For example, metabolism the extremes of age differs, increasing from fetal to age 2 and
is often the major route of drug elimination, and metabolism declining in the elderly. Hepatic drug biotransformation may
can occur in intestinal epithelia right after drug absorption, be impaired directly in hepatic disease, and indirectly in renal
affecting “net” absorption, or bioavailability. The liver is the disease. Understanding drug metabolism is essential for under-
primary site of biotransformation, and renal metabolism may standing anesthetic pharmacokinetics, clinical effects, and side
be significant for certain drugs. effects, and for individualizing patient care.
85
therapies: pharmacogenetic, 25. Madan A, Usuki E, Burton LA, Ogilvie BW,

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Section 1

transport is sometimes referred to as phase III metabolism.

Drug or Active Inactive Figure 6.1. Consequences of drug biotransfor-

A Primary blockers), hepatic clearance (CLH), defined as the volume of blood

1) Hepatocytes of the liver Figure 6.3. Metabolism of a theoretical drug after

dextromethorphan * dextrorphan Figure 6.4. Role of CYP2D6 and CYP3A4 in the

Table 6.3. Geographic variability in the frequency of CYP2D6 phenotypes

Region Poor Intermediate Extensive Ultrarapid

Other CYPs importance, because it metabolizes numerous small molecules,

MDZ Clearance (L/kg/hr)

Geriatrics Applied clearance concepts

Low extraction thiopental, diazepam, lorazepam, Pharmacogenetics

100 10 Figure 6.6. Influence of hepatic extraction ratio of

Plasma Fentanyl (ng/ml)

tering the CYP3A inhibitor troleandomycin prior to

1000 Figure 6.8. Influence of CYP2D6 activity on

EM Control codeine metabolism and analgesia. (A) Pharmaco-

6 who received morphine or codeine. Morphine anal-

therapies: pharmacogenetic, 25. Madan A, Usuki E, Burton LA, Ogilvie BW,

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