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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5849_Библиотеки_им_академика_М_И_Перельмана
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4.4.6.1 Phase I Metabolism Phase I metabolic reactions include oxidation,
reduction, and hydrolysis. These reactions serve to increase the hydrophilicity of
a compound by exposing or introducing hydrophilic functional groups, thus facilitating excretion [126]. Metabolites formed by Phase I processes may be sequentially
metabolized by additional Phase I metabolism or by conjugation reactions.
Oxidation The principal drug-metabolizing enzymes responsible for oxidation
reactions include cytochrome P450 (CYP) enzymes, flavin monooxygenases (FMO)
and several others. CYP enzymes are by far the most important for metabolism of
drugs [127, 128] and are the major focus of medicinal chemistry strategies to reduce
metabolism by alteration of metabolically labile sites.
CYP ENZYMES AND THEIR CLINICAL IMPORTANCE CYP enzymes are capable of catalyzing
a variety of oxidation reactions. It has been estimated that CYP enzymes contribute to
the metabolism of 75% of marketed drugs, and that five major CYP isoforms
(CYP1A2, 2C9, 2C19, 2D6, and 3A4) are involved in 95% of all Phase I reactions [129]. CYP3A4 is the most important CYP isoform for the metabolism of drugs
and is involved as a major or minor drug-metabolizing enzyme in more than half of all
drugs [130]. The human CYP isoforms most often involved in the metabolism of drugs
along with characteristics of typical substra tes are listed in Table 4.4. In general, the
TABLE 4.4 Characteristics of Human CYP Isoforms and their Substrates
a
CYP
% Total
Hepatic
CYP
b
Substrate
Range
of log P
Substrate
Average
log P
Substrate Molecular
Characteristics
Typical
Substrate
1A2 12 0.08–3.61 2.01 Poly(hetero)aromatic
amines and amides
MeIQ
c
2A6 4 0.07–2.79 1.44 Relatively small neutral
molecules
Losigamone
2B6 1 0.23–4.89 2.54 Basic (unionized)
compounds
Bupropion
2C8
d
0.06–6.98 3.38 Acidic (ionized)
compounds
Rosiglitazone
2C9
d
0.89–5.18 3.20 Acidic (unionized)
compounds
Naproxen
2C19
d
1.49–4.42 2.56 Amides and amines Proguanil
2D6 4 0.75–5.04 3.08 Basic (ionized)
compounds
Propranolol
2E1 6 –1.35 to 3.63 2.07 Small neutral molecules 4-Nitrophenol
3A4 30 0.97–7.54 3.10 Large neutral molecules Nifedipine
a
Adapted from Ref. 131.
b
Adapted from Ref. 132.
c
MeIQ ¼ 2-amino-3,4-dimethylimidazo[4,5-f ]quinoline.
d
Total CYP2C is approximately 20%; quantification of individual isoforms is limited by antibody cross-
reactivtiy.
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binding affinity of a substrate to CYP enzymes is determined by the log P and the
number of hydrogen bond donor and acceptor atoms [131]. Additional factors
affecting which CYP isoforms are likely to contribute to the metabolism of a
compound include molecular weight, planarity, and acidity/basicity. Because of
overlapping substrate specificity, compounds can be substrates of multiple CYP
enzymes, and the site of metabolism may be the same or can vary.
CYP1A2 CYP1A2 tends to oxidize small, planar lipophilic compounds such as
caffeine and phenacetin and is often a minor or secondary contributor to the
metabolism of a drug. It is additionally important because it plays a role in the
metabolic activation of some carcinogens.
CYP2C8 CYP2C8 has a larger active site than the other CYP2C enzymes and tends to
metabolize medium to large molecular weight acidic and lipophilic compounds.
CYP2C8 has substrate affinity that overlaps somewhat with CYP3A. Paclitaxel,
amiodarone, and rosigl itazone are examples of CYP2C8 substrates.
CYP2C9 CYP2C9 preferentially metabolizes compounds that are hydrophobic and
weakly acidic, including drugs such as phenytoin, ( S )-warfarin, and numerous
nonsteroidal anti-inflammatory drugs.
CYP2C19 CYP2C19 tends to metabolize medium to large molecular weight lipo-
philic amine and amide compounds such as (S)-mephenytoin and omeprazole and has
substrate affinity that overlaps somewhat with CYP3A.
CYP2D6 CYP2D6 preferentially metabolizes ionized basic compounds and often
oxidizes metabolizable sites 7 or 9 A˚from a basic nitrogen. Many drugs are
metabolized by CYP2D6 including most beta andrenergic blocking drugs and a
wide variety of psychotherapeutic agents.
CYP3A4/5 CYP3A4 is the most abundant human CYP isoform and is the most
important human drug-metabolizing enzyme due to its relative abundance combined
with its large active site and broad substrate specificity for metabolizing lipophilic
molecules. The closely related CYP3A5 has similar metabolic properties, although it
is only expressed in appro ximately one-fourth of humans. In those humans possessing
this isoform, expression levels are typically only one-third as high as for CYP3A4.
CYP2A6, CYP2B6, AND CYP2E1 These are minor CYP isoforms that can contribute to
the metabolism of drugs but are not usually identified as the major contributor.
CYP2E1 is important for the metabolism of many low molecular weight compounds,
including organic solvents and some inhalable anesthetics.
FLAVIN MONOOXYGENASE FMO enzymes catalyze the oxidation of nucleophilic
nitrogen, sulfur, and phosphorous heteroatoms present in a variety of drugs [133].
The most important FMO reactions are the oxidation of tertiary amines to N-oxides,
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the oxidation of secondary amines to hydroxylamines, and the oxidation of thiols,
thiones, and thioethers to S-oxides. Many oxidation reactions catalyzed by FMO can
also be cat alyzed by CYP, and experimental procedures have been developed
to determine the contribution of FMO compared to CYP enzymes for a specific
reaction.
OTHER ENZYMES PREFORMING OXIDATION REACTIONS Other important enzymes that are
capable of performing oxidation reactions of drugs include alcohol dehydrogenase,
aldehyde dehydrogenase, aldehyde oxidase, xanthine oxidase, monoamine oxidase,
and diamine oxidase [126].
Reduction Reduction reactions include azo, nitro, carbonyl, disulfide, sulfoxide,
quinone reductions, and also reductive dehalogenation reactions. The drug-metabolizing enzymes responsible for these reduction reactions vary with the type of
reduction. Azo- and nitro-group reductions can be performed by intestinal microflora,
CYP enzymes, and NAD(P)H-quinone oxidoreductase. Carbonyl group reductions
can be catalyzed by alcohol dehydrogenase and a family of carbonyl reductases.
Disulfides can be reduced in a reaction involving glutat hione-S-transferase, sulfoxide,
and N-oxide reductions can be catalyzed by CYP. Quinone reductions are catalyzed
by NAD(P)H-quinone oxidoreductase, and reductive dehalogenation reactions are
catalyzed by CYP.
Hydrolysis The main enzymes responsible for hydrolysis reactions are carboxylesterases, peptidases, and epoxide hydrolases. Hydrolysis reactions are
especially important for the metabolism of prodrugs and can occur in blood, intestine,
or liver.
4.4.6.2 Species Differences in Phase I Metabolism The differences in homology
and expression levels of Phase I metabolizing enzymes between humans and preclinical animal species are great enough that cross-species metabolism is not predictable.
This is especially true of CYP enzyme in which it has been shown experimentally using
site-directed mutagenesis studies that a single amino acid substitution in the active site
of an enzyme can change the catalytic specificitysuch that a different oxidationproduct
is formed. Therefore, human in vitro drug-metabolizing systems are considered to be
the most relevant predictor of human metabolism, and likewise, in vitro systems for
other preclinical animal species should be used to predict their respective in vivo
metabolic rates and/or profiles. Species differences in Phase I metabolism are reviewed
elsewhere [134, 135].
4.4.6.3 Phase II Metabolism (Conjugation) Phase II metabolic reactions add
conjugate functionalities that result in a large increase in hydrophilicity, usually
greater than that achieved by Phase I reactions [126]. Compounds do not need to
undergo Phase I metabolism prior to Phase II. Metabolites formed by Phase II
processes are often vastly more amenable to excretion than the parent compound, but
still may be sequentially metabolized by additional Phase I or II reactions.
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Glucuronidation Glucuronidation represents a major biotransformation pathway
for drugs, as well as steroid, bile acids, bilirubin, and other dietary components [136,
137]. Uridine-diphoshphate glucuronosyltransferase (UGT) enzymes utilize uridinediphoshphate (UDP) glucuronic acid as a cofactor, which can be conjugated with
compounds containing an electron-rich heteroatom such as O, S, or N. Hydroxyl and
carboxyl functionalities are most often subject to glucuronidation. Glucuronidation of
carboxylic acids can result in acyl migration of the glucuronide and may lead to the
formation of reactive metabolites.
Sulfation Many of the same substrates that undergo O-glucuronidation can also be
metabolized to sulfate conjugates by sulfotranserases using 3
0
-phosphoadenosine-50phosphosulfate (PAPS) as the cofactor. The conjugation reaction is carried out by the
transfer of SO
3
from PAPS to the drug compound.
Glutathione Conjugation Conjugation with glutathione by glutathione-S-transferase represents a major detoxification mechanism by reducing reactive metabolite
concentrations in circulation.
Other Phase II Processes Other important Phase II reactions include amino acid
conjugation, acylation, and methylation.
Species Differences in Phase II Metabolism As with Phase I metabolic reactions,
numerous species differences exist between Phase II metabolism reactions in humans
and preclinical animal species [138]. Some species differences are mainly quantitative, in which differing amounts of the same conjugate metabolite are formed, for
example, guinea pigs have an unusually high capacity for methylation compared to
human. Others species differences involve a complete inability to catalyze a specific
metabolic reaction, for example, dogs cannot acetylate aromatic amines and pigs
cannot catalyze sulfate conjugations [135]. In some cases these species differences in
metabolism can lead to differences in toxicity or carcinogenicity.
4.4.6.4 Extrahepatic Metabolism Although liver is the major site of metabolism
for drugs and is the organ most thoroughly studied, other organs and tissues can also
contribute to the metabolism of drugs [139]. Small intestine, kidney, and lung contain
significant amounts of drug-metabolizing enzymes, although, in terms of functional
enzyme capacity, these organs are one to two orders of magnitude lower compared to
the liver. In particular, CYP enzymes are known to be distributed throughout the body
and are found in most tissues, including brain and skin, albeit often at low levels of
expression.
4.4.7 Excretion
Excretion of unchanged compound is the primary mechanism of elimination for many
drugs and other xenobiotic substances, especially for hydrophilic compounds and
those that are charged at physiological pH. Quantitatively, excretion into urine and
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feces (via secretion into bile) comprises the majority of drug and metabolite removal
from the body, except for some low molecular weight compounds, such as inhalable
anesthetics, which can be excreted by exhalation from the lungs.
4.4.7.1 Renal Excretion Drugs that have polar functionality and molecular
weight <500 are water soluble and predominantly excreted in the kidney. Recently,
an analysis of human renal clearance data for a set of 391 compounds showed that
renal clearance contributes to >50% of total body clearance for 31% of the
compounds [140]. The excretory functional unit of the kidney is the nephron, which
is composed of the glomerulus, proximal tubule, loop of Henle, distal tubule, and the
collecting tubule. The three mechanisms involved in drug excretion through the
kidney are glomerular filtration, tubular reabsorption, and active secretion. The renal
transporters that are important for active secretion are shown in Figure 4.11.
Glomerular Filtration Glomerular filtration is the nonselective passive process by
which many drugs and small molecules are filtered through the glomer ulus of the
nephron. This process is driven by hydrostatic pressure formed in the capillaries.
Tubular Reabsorption Tubular reabsorpti on takes place after glomerular filtration
and occurs all along the renal tubule. Lipophilic drugs undergo extensive reabsorption, while hydrophilic drugs and compounds are not reabsorbed and are more readily
excreted in the urine.
Active Tubular Secretion For acidic and basic compounds ionized at physiological
pH, active tubular secretion is the most important excretion process. The active
Figure 4.11 Renal transporters.
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secretion is performed by transport proteins in the proximal tubule, with different sets
of transporters existing for acids and bases.
The Role of Lipophilicity in Renal Excretion The extent of reabsorption of drug in
the kidney depends on both the lipophilicity and ionization of the drug. If a drug has
sufficient lipophilicity, the drug is reabsorbed by passive diffusion and concentrated as
the kidney reabsorbs water. For neutral compounds, reabsorption only occurs at log
D
7.4
values >0 and excretion into urine is more likely as log D
7.4
decreases [79].
The Role of Charge in Renal Excretion Because tubular pH (6.5) is often more
acidic than plasma pH (7.4), the renal clearance of acidic drugs may be higher than
their log D
7.4
might suggest, and conversely, the renal clearance of basic drugs may be
lower than their log D
7.4
might suggest. Particularly for lipophilic charged compounds, the renal excretion can be very high due to interactions with active tubular
secretion transporters [79].
4.4.7.2 Biliary Excretion In addition to renal excretion, the other major route is
hepatic excretion into the bile, which is produced in the liver and flows into the
intestinal tract. As opposed to the kidney, the liver cannot passively filter chemicals
but can actively secrete chemicals into bile and eventually eliminate them via
excretion of feces. Biliary secretion of a chemical may not result in the immediate
elimination of chemical from the body because of hepatobiliary recirculation, which
is discussed in more detail in the section “Enterohepatic Recirculation of Drugs”.
Bile Composition The production and recirculation of bile is the main excretory
function of the liver. Bile is composed primarily of bile salts and smaller amounts of
cholesterol, phospholipids, bilirubin, protein, and other components [141]. The bile
salts function as detergents that dissolve dietary fat and also solubilize lipophilic drugs.
Compound Properties Leading to Biliary Excretion Anions, cations, and neutral
compounds containing both hydrophilic and lipophilic groups can be secreted into
bile. Generally, the molecular weight must be >300 for biliary secretion to occur
because lower molecular weight compounds are generally reabsorbed before being
secreted into the bile duct. In humans, the threshold for preferential excretion of
compounds into bile is a MW in the 500–600 Da range [142]. This threshold varies
across species and is as low as approximately 235 Da in rats.
The Role of Transporters in the Biliary Secretion of Drugs For drugs that cannot exit
hepatocytes by simple passive diffusion into the plasma, a number of transport proteins
exists that actively secrete the drugs and/or their metabolites into the bile [125].
Enterohepatic Recirculation of Drugs An issue that can affect both drugs and
metabolites, particularly glucuronide conjugates, is enterohepatic (or hepatobiliary)
recycling (EHR, see Section 5.2.1.5). After a drug is conjugated with glucuronic acid
to form a glucuronide metabolite, the metabolite can be secreted into bile, which flows
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to the gall bladder and is released into the small intestine. In the intestine, the
glucuronide conjugate can be hydrolyzed back to the parent compound by b-glucuronidases present in intestinal bacteria. The parent compound can then be reabsorbed
and returned to circulating blood and the liver where it can be metabolized and the
cycle repeats [143].
4.5 DRUG INTERACTIONS
Adverse drug reactions are undesirable and can result in the clinical failure of drug
candidates and can alsolead to alterationofthe dosing regimen of approved productsand
even withdrawal from the market. Although individual drugs can cause adverse drug
reactions, many adversereactionsresult from DDI due to concomitantadministration of
multiple medicinal products. The two main categories of DDI are pharmacological and
pharmacokinetic. Pharmacological DDI occurs when one or more drugs alters the
pharmacological effect of another. Examples of this type of DDI include the synergistic
and additive effect of multiple central nervous system depressants, resulting in severe
respiratory depression; and the inhibition of platelet aggregation by nonsteroidal antiinflammatory drugs, leading to increased bleeding when anticoagulants are co-administered. Reviews of pharmacological DDI are provided elsewhere [144].
Pharmacokinetic DDI affect the disposition of a drug and can occur when any
ADME process is interfered with, including absorption, distribution, metabolism,
and/or excretion.
4.5.1 Absorption-Driven DDI
Absorption can be affected by the chemical interaction of drugs that complex or
chelate with each other, by drugs that change the rate of gastric emptying, drugs that
alter the pH of gastrointestinal fluids, and drugs that alter the composition of intestinal
microflora, for example, antibiotics. In addition, drugs and excipients can interact in
the gastrointestinal tract and affect drug absorption. Most clinically important
drug–excipient interactions have been shown to affect disintegration and/or dissolution processes [145].
4.5.2 Distribution-Driven DDI
Distribution processes are typically only affected when drugs displace each other from
plasmaprotein bindingsites[146].Thistypeofdrug interactiononly resultsin significant
consequences in very limited situations and is not a major source of clinical DDI.
4.5.3 Excretion-Driven DDI
Excretion of drugs can be inhibited due to interactions with renal or biliary
transporters. Renal excretion of ionizable compounds can be either reduced or
increased by concomitant administration of drugs that affect the pH of urine.
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4.5.4 Metabolism-Driven DDI
Metabolic DDI due to perturbations of drug metabolism are by far the major cause of
pharmacokinetic DDI and have lead to the withdrawal of numerous marketed
products [147]. Metabolic DDI are discussed in detail below, and are a main focus
of medicinal chemistr y strategies to reduce comp ound attrition in Pharmaceutical
Discovery and Development.
4.5.4.1 DDI via Inhibition of Drug-Metabolizing Enzymes Metabolic DDI
occurs when a drug causes either an increase or decrease of systemic exposures of
other drugs due to alterations of drug metabolism, or is susceptible to an increase or
decrease of its own systemic exposures due to effects on its metabolism by other
concomitantly administered drugs. Multiple strategies are used to screen drug
candidates for metabolic DDI potential and are tailored to the discovery or development stage. The FDA has issued a Guidance to Industry that provides suggestions
for approaches to studying the potential for metabolic DDI using in vitro techniques [148, 149] (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf).
Perpetrator DDI The most clinically significant type of DDI occurs when a drug is a
potent inhibitor (perpetrator) of one or more CYP enzymes. The consequence of this
inhibition can result in a severe reduction of drug-metabolizing capacity and the loss
of the major elimination mechanism for many other drugs that are metabolized by the
same enzymes, which can lead to toxic or even lethal increases in circulating blood
concentrations. This is especially the case for potent inhibitors of CYP3A4, such as
antifungal drugs and some antiviral agents.
Although metabolic DDI can be caused by inhibition of drug-metabolizing
enzymes other than CYPs, clinically relevant examples are rare. Glucuronidation
is an elimination mechanism for approximately one in ten of the most highly
prescribed drugs, yet the likelihood of metabolic DDI is low for drugs cleared by
glucuronidation [150].
Victim DDI Drugs that are eliminated via metabolism by a single drug-metabolizing enzyme can greatly increase circulating blood concentrations if that metabolic
pathway is inhibited significantly.This type of drug is often referred to as the “victim”
of a metabolic DDI such as the interaction between ketoconazole and terfenadine.
Ketoconazole is a potent inhibitor of CYP3A4, and terfenadine is dependent on
CYP3A4 metabolism as its sole route of elimination. Terfenadine is thus the victim of
the ketoconazole inhibition, and this clinically significant DDI eventually resulted in
the withdrawal of terfenadine from the market.
4.5.4.2 Metabolism by Polymorphic CYPs Another type of undesirable metabolic drug interaction occurs when a drug is eliminated primarily via metabolism of a
polymorphically expressed human CYP isoform; most notably CYP2C19 and
CYP2D6. For each of these two CYP isoforms a significant fraction of the population
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exhibits a poor metabolizer phenotype. The result of a drug relying on one of these
enzymes for its elimination can lead to greatly increased circulating blood concentrations in those subjects who completely lack or possess significantly reduced drugmetabolizing capacity for that enzym e. In this case the increased risk of toxicity is not
caused by an interaction between two drugs, but rather the drug and its mechanism of
elimination.
4.5.4.3 DDI via Induction of Drug-Metabolizing Enzymes Induction occurs
when drug metabolism capacity is increased due to an increase in intracellular
metabolizing enzymes occurring primarily in the liver, but also in the lung, small
intestine, kidney, and other tissues. Unlike inhibition of drug-metabolizing enzymes
that can happen immediately, induction takes longer (several days) to achieve a higher
steady-state level of enzyme activity. The mos t important clinical example of
induction is the effect of the potent CYP3A4 inducer rifampicin on reducing the
systemic exposure of the tissue rejection drugs cyclosporine and tacrolimus, which
have a very narrow therapeutic index [151]. Rifampicin causes an increase in CYP3A4
activity that reduces blood concentrations of these immunosuppressant drugs and can
lead to tissue rejection. In the pharmaceutical industry, induction of CYP3A4 is the
greatest concern for DDI and drug candidates are often compared to rifampicin to
ascertain their potential to cause a clinically relevant CYP3A4 induction.
Cause of Induction and Sequence of Events CYP induction is caused by a sequence
of events starting with the binding of a drug or dietary component to a nuclear receptor
such as PXR or CAR, followed by an increase in gene transcription, protein
translation, and finally, an increase in the level of functional drug-metabolizing
enzyme [152]. The induction process takes several days to occur and usually is not
maximal in humans until 10–14 days.
Assessment of Potential for CYP Induction Strategies for assessment of CYP
induction are employed at every step of the sequence. The highest throughput method
is to assess binding of compound to the pregnane-X receptor (PXR), the human
nuclear receptor most responsible for upregulation of CYP3A4, using a reporter gene
assay. The definitive and most predictive assay uses cultured primary human
hepatocytes. Compounds of interest are incubated with hepatocytes and the increases
in CYP3A4 mRNA and protein are measured. Increases in functional drug-metabolizing capacity are assessed by incubating the induced cells with a CYP3A4 probe
substrate and measuring the formation of marker metabolites.
Issues with Prediction of CYP Induction Assessment of CYP induction potential
often results in low confidence in the quantitative prediction of induction, even when
using human in vitro systems, because of the high variability of induction response in
the human population. The ability to form structure–activity relationships with PXR is
challenging due to the wide variety of chemical structures that are able to bind to the
receptor. In addition, induction of CYP3A4 has been shown to be a species specific
process due to species differences in the ligand binding domain of PXR [153]. For
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example, rifampicin is known to be a potent inducer of CYP3A in human but not in rat.
Conversely, pregnenolone 16a-carbonitrile is a very potent inducer of CYP3A in rat
but not in human. Prediction of human induction potential from preclinical animal in
vivo exposure data may not be predictive.
4.5.5 Tools for Studying Drug Metabolism
A variety of tools can be utilized to investigate drug metabolism in the various stages
of drug discovery and development:
.
In vivo studies
.
In situ perfused organs
.
Liver slices
.
In vitro cell-based systems (hepatocyte suspensions)
.
In vitro subcellular fractions (microsomes, S9, cytosol)
.
In vitro recombinant drug-metabolizing enzymes
.
In silico tools.
Usually these tools are used in combination to address different aspects of drug
metabolism. Understanding of the advantages and disadvantages of certain tools as
well as their best application to the projects of different stages is critical for medicinal
chemists and their ADME partners.
Most of the tools are derived from liver tissue because the liver is the major site of
drug metabolism, although preparations from other tissues such as kidney, intestine,
or lung may also be used in order to elucidate the contribution of metabolism in those
tissues.
4.5.5.1 In Vivo Studies in Animals Pharmacokinetic clearance data from intravenously dosed preclinical animals can be used to assess the rate of hepatic
metabolism, provided it can be determined that hepatic metabolism is the major
route of elimination and excretion is minor. For screening a large number of
compounds, rat is the species utilized most often, however the preclinical species
most relevant to human should be used if possible. Animal pharmacokinetic
studies are also used as a source of in vivo metabolites, which can be isolated from
plasma, urine, bile, feces, and other fluids or tissues. Profiling parent and metabolites
in plasma and excreta using radiolabeled drug in an in vivo mass balance study is
considered more definitive because it does not require prior knowledge of expected
metabolites.
The extent of first-pass metabolism by the liver may be evaluated in vivo by
comparing the plasma AUC of the drug-dosed PO with that following direct infusion
into the portal vein system. The use of various chemical inhibitors such as
1-aminobenzotriazole, a potent, nonspecific inhibitor of CYP enzymes, can be used
to assess CYP contributions to metabolism, although care should be taken in
understanding the specificity of inhibition [154].
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