The dose and frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors as well as nongenetic variables, such as commensal gut microbiota, age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows summarizes the most important of these variables.
Individual differences in metabolic rate depend on the nature of the drug itself. Thus, within the same population, steady-state plasma levels may reflect a 30-fold variation in the metabolism of one drug and only a twofold variation in the metabolism of another.
Genetic factors that influence enzyme levels account for some of these differences, giving rise to “genetic polymorphisms” in drug metabolism (see also Chapter 5). The first examples of drugs found to be subject to genetic polymorphisms were the muscle relaxant succinylcholine, the antituberculosis drug isoniazid, and the anticoagulant warfarin. A true genetic polymorphism is defined as the occurrence of a variant allele of a gene at a population frequency of ≥ 1%, resulting in altered expression or functional activity of the gene product, or both. Well-defined and clinically relevant genetic polymorphisms in both phase I and phase II drug-metabolizing enzymes exist that result in altered efficacy of drug therapy or adverse drug reactions (ADRs). The latter frequently necessitate dose adjustment (Table 4–4), a consideration particularly crucial for drugs with low therapeutic indices.
TABLE 4–4Some examples of genetic polymorphisms in phase I and phase II drug metabolism. ||Download (.pdf) TABLE 4–4 Some examples of genetic polymorphisms in phase I and phase II drug metabolism.
|Enzyme Involved ||Defect ||Genotype ||Drug and Therapeutic Use ||Clinical Consequences1 |
|CYP1A2 ||N-Demethylation ||EM ||Caffeine (CNS stimulant) ||Reduced CNS stimulation due to increased gene inducibility and thus increased metabolism/clearance in cigarette smokers and frequent ingesters of omeprazole. |
| ||N-Demethylation ||PM ||Caffeine (CNS stimulant) ||Enhanced CNS stimulation. |
|CYP2A6 ||Oxidation ||PM ||Nicotine (cholinoceptorstimulant) ||Nicotine toxicity. Lesser craving for frequent cigarette smoking. |
| ||Oxidation ||EM ||Nicotine (cholinoceptorstimulant) ||Increased nicotine metabolism. Greater craving for frequent cigarette smoking. |
| ||Oxidation ||PM ||Coumarin (anticoagulant) ||Increased risk of bleeding. |
| ||Oxidation ||EM ||Coumarin (anticoagulant) ||Increased clearance. Greater risk of thrombosis. |
|CYP2B6 ||Oxidation, N-Dechloroethylation ||PM ||Cyclophosphamide, ifosfamide (anti-cancer) ||Reduced clearance. Increased risk of ADRs. |
| ||Oxidation ||PM ||Efavirenz, nevirapine (anti-HIV) ||Reduced clearance. Increased risk of ADRs. |
|CYP2C8 ||Hydroxylation ||PM ||Repaglinide, rosiglitazone, pioglitazone (antidiabetic) ||Reduced clearance. Increased risk of ADRs. |
| ||Hydroxylation ||PM ||Paclitaxel (anti-cancer) ||Reduced clearance. Increased risk of ADRs (myelosuppression). |
| ||N-Deethylation/N-Dealkylation ||PM ||Amodiaquine, chloroquine (antimalarial) ||Reduced clearance. Increased risk of ADRs. |
| ||N-Deethylation ||PM ||Amiodarone (antiarrhythmic) ||Reduced clearance. Increased risk of ADRs. |
|CYP2C9 ||Hydroxylation ||PM ||Celecoxib, diclofenac, flurbiprofen, S-ibuprofen (NSAIDs) ||Reduced clearance. Increased risk of ADRs. |
| ||Hydroxylation ||PM ||S-Warfarin, S-acenocoumarol (anticoagulants) ||Enhanced bleeding risk. Clinically highly relevant. Dose adjustment required. |
| ||Hydroxylation ||PM ||Tolbutamide (antidiabetic) ||Cardiotoxicity. |
| ||Hydroxylation ||PM ||Phenytoin (antiepileptic) ||Nystagmus, diplopia, and ataxia. |
|CYP2C19 ||N-Demethylation ||PM ||Amitriptyline, clomipramine (antidepressants) ||Reduced clearance. Increased risk of ADRs. Dose adjustment required. |
| ||Oxidation ||PM ||Moclobemide (MAOI) || |
| ||N-Demethylation ||PM ||Citalopram (SSRI) ||Increased risk of gastrointestinal side effects. |
| ||O-Demethylation ||PM ||Omeprazole (PPI) ||Increased therapeutic efficacy. |
| ||Hydroxylation ||PM ||Mephenytoin (antiepileptic) ||Overdose toxicity. |
| ||N-Demethylation ||EM ||Escitalopram (antidepressants) ||Increased gene transcription resulting in increased activity and thus reduced therapeutic efficacy. |
| ||O-Demethylation ||EM ||Omeprazole (PPI) ||Reduced therapeutic efficacy. |
| ||Hydroxylation ||EM ||Tamoxifen (anti-cancer) ||Increased metabolic activation, increased therapeutic efficacy; reduced risk of relapse. Dose adjustment required. |
| ||Oxidative cyclization ||EM ||Chlorproguanil (antimalarial) ||Increased metabolic activation, increased therapeutic efficacy. Dose adjustment required. |
| ||Oxidation ||EM ||Clopidogrel (antiplatelet) ||Increased metabolic activation, increased therapeutic efficacy. Dose adjustment required. |
|CYP2D6 ||Oxidation ||PM ||Bufuralol (β-adrenoceptor blocker) ||Exacerbation of β blockade, nausea. |
| ||O-Demethylation ||PM ||Codeine (analgesic) ||Reduced metabolic activation to morphine and thus reduced analgesia. |
| ||Oxidation ||PM ||Debrisoquin (antihypertensive) ||Orthostatic hypotension. |
| ||N-Demethylation ||PM ||Nortriptyline (antidepressant) ||Reduced clearance. Increased risk of ADRs. |
| ||Oxidation ||PM ||Sparteine ||Oxytocic symptoms. |
| ||O-Demethylation ||PM ||Dextromethorphan (antitussive) ||Reduced clearance. Increased risk of ADRs. |
| ||O-Demethylation ||PM ||Tramadol (analgesic) ||Increased risk of seizures. |
| ||Hydroxylation ||PM ||Tamoxifen (anti-cancer) ||Reduced metabolic activation to the therapeutically active endoxifen and thus reduced therapeutic efficacy. |
| ||O-Demethylation ||UM ||Codeine (analgesic) ||Increased metabolic activation to morphine and thus increased risk of respiratory depression. |
| ||N-Demethylation ||UM ||Nortriptyline (antidepressant) ||Reduced therapeutic efficacy due to increased clearance. |
| ||O-Demethylation ||UM ||Tramadol (analgesic) ||Reduced therapeutic efficacy due to increased clearance. |
|CYP3A4 || ||PM? ||All drugs metabolized by this enzyme would be potentially affected ||Reduced clearance. Dose adjustment may be required to avoid drug-drug interactions. |
|CYP3A5 || ||PM? ||Saquinavir, and other CYP3A substrates ||Usually less catalytically active than CYP3A4. A higher frequency of a functional CYP3A5*1 allele is seen in Africans than in Caucasians; the latter most often carry the defective CYP3A5*3 allele. This may significantly affect therapeutics of CYP3A substrates in CYP3A5*1 or CYP3A5*3 homozygous individuals. |
|ALDH ||Aldehyde dehydrogenation ||PM ||Ethanol (recreational drug) ||Facial flushing, hypotension, tachycardia, nausea, vomiting. |
|BCHE ||Ester hydrolysis ||PM ||Succinylcholine (muscle relaxant) ||Prolonged apnea. |
| || || ||Mivacurium (neuromuscular blocker) ||Prolonged muscle paralysis. |
| || || ||Cocaine (CNS stimulant) ||Increased blood pressure, tachycardia, ventricular arrhythmias. |
|GST ||GSH-conjugation ||PM ||Acetaminophen (analgesic), Busulfan (anti-cancer) ||Impaired GSH conjugation due to gene deletion. |
|NAT2 ||N-Acetylation ||PM ||Hydralazine (antihypertensive) ||Lupus erythematosus-like syndrome. |
| ||N-Acetylation ||PM ||Isoniazid (antitubercular) ||Peripheral neuropathy. |
|TPMT ||S-Methylation ||PM ||6-Thiopurines (anti-cancer) ||Myelotoxicity. |
|UGT1A1 ||Glucuronidation ||PM ||Bilirubin (heme metabolite) ||Hyperbilirubinemia. |
| || || ||Irinotecan (anti-cancer) ||Reduced clearance. Dose adjustment may be required to avoid toxicity (GI dysfunction, immunosuppression). |
A. Phase I Enzyme Polymorphisms
Genetically determined defects in the phase I oxidative metabolism of several drugs have been reported (Table 4–4; see also Chapter 5). These defects are often transmitted as autosomal recessive traits and may be expressed at any one of the multiple metabolic transformations that a chemical might undergo. Human liver P450s 3A4, 2C9, 2D6, 2C19, 1A2, and 2B6 are responsible for about 75% of all clinically relevant phase I drug metabolism (Figure 4–4), and thus for about 60% of all physiologic drug biotransformation and elimination. Thus, genetic polymorphisms of these enzymes, by significantly influencing phase I drug metabolism, can alter their pharmacokinetics and the magnitude or the duration of drug response and associated events.
Three P450 genetic polymorphisms have been particularly well characterized, affording some insight into possible underlying molecular mechanisms, and are clinically noteworthy, as they require therapeutic dosage adjustment. The first is the debrisoquin-sparteine oxidation type of polymorphism, which apparently occurs in 3–10% of Caucasians and is inherited as an autosomal recessive trait. In affected individuals, the CYP2D6-dependent oxidations of debrisoquin and other drugs (Table 4–2; Figure 4–6) are impaired. These defects in oxidative drug metabolism are probably co-inherited. The precise molecular basis for the defect appears to be faulty expression of the P450 protein due to either defective mRNA splicing or protein folding, resulting in little or no isoform-catalyzed drug metabolism and thereby conferring a poor metabolizer (PM) phenotype. This PM phenotype correlates with a higher risk of relapse in patients with breast cancer treated with tamoxifen, an anticancer drug that relies on its CYP2D6-dependent metabolic activation to endoxifen for its efficacy. More recently, however, another polymorphic genotype has been reported that results in ultrarapid metabolism of relevant drugs due to the presence of CYP2D6 allelic variants with up to 13 gene copies in tandem. This ultrarapid metabolizer (UM) genotype is most common in Ethiopians and Saudi Arabians, populations that display it in up to one third of individuals. As a result, these subjects require twofold to threefold higher daily doses of nortriptyline (an antidepressant and a CYP2D6 substrate) to achieve therapeutic plasma levels. The poor responsiveness to antidepressant therapy of the UM phenotype also clinically correlates with a higher incidence of suicides relative to that of deaths due to natural causes in this patient population. Conversely, in these UM populations, the prodrug codeine (another CYP2D6 substrate) is metabolized much faster to morphine, often resulting in undesirable adverse effects of morphine, such as abdominal pain. Indeed, intake of high doses of codeine by a mother of the ultrarapid metabolizer type was held responsible for the morphine-induced death of her breast-fed infant.
Genetic polymorphism in debrisoquin 4-hydroxylation by CYP2D6 in a Caucasian population. The semilog frequency distribution histogram of the metabolic ratio (MR; defined as percent of dose excreted as unchanged debrisoquin divided by the percent of dose excreted as 4-hydroxydebrisoquin metabolite) in the 8-hour urine collected after oral ingestion of 12.8 mg debrisoquin sulfate (equivalent to 10 mg free debrisoquin base). Individuals with MR values >12.6 were phenotyped as poor metabolizers (PM, red bars), and those with MR values <12.6 but >0.2 were designated as extensive metabolizers (EM, blue bars). Those with MR values <0.2 were designated as ultrarapid metabolizers (URM, green bars) based on the MR values (0.01–0.1) of individuals with documented multiple copies of CYP2D6 allelic variants resulting from inherited amplification of this gene. (Data from Woolhouse et al: Debrisoquin hydroxylation polymorphism among Ghanians and Caucasians. Clin Pharmacol Ther 1979;26:584.)
The second well-studied genetic drug polymorphism involves the stereoselective aromatic (4)-hydroxylation of the anticonvulsant mephenytoin, catalyzed by CYP2C19. This polymorphism, which is also inherited as an autosomal recessive trait, occurs in 3–5% of Caucasians and 18–23% of Japanese populations. It is genetically independent of the debrisoquin-sparteine polymorphism. In normal “extensive metabolizers” (EMs) (S)-mephenytoin is extensively hydroxylated by CYP2C19 at the 4 position of the phenyl ring before its glucuronidation and rapid excretion in the urine, whereas (R)-mephenytoin is slowly N-demethylated to nirvanol, an active metabolite. PMs, however, appear to totally lack the stereospecific (S)-mephenytoin hydroxylase activity, so both (S)- and (R)-mephenytoin enantiomers are N-demethylated to nirvanol, which accumulates in much higher concentrations. Thus, PMs of mephenytoin show signs of profound sedation and ataxia after doses of the drug that are well tolerated by normal metabolizers. Two defective CYP2C19 variant alleles (CYP2C19*2 and CYP2C19*3), the latter predominant in Asians, are largely responsible for the PM genotype. The molecular bases include splicing defects resulting in a truncated, nonfunctional protein. CYP2C19 is responsible for the metabolism of various clinically relevant drugs (Table 4–4). Thus, it is clinically important to recognize that the safety of each of these drugs may be severely reduced in persons with the PM phenotype. On the other hand, the PM phenotype can notably increase the therapeutic efficacy of omeprazole, a proton-pump inhibitor, in gastric ulcer and gastroesophageal reflux diseases (see Chapter 5 for additional discussion of the CYP2C19 polymorphism).
Another CYP2C19 variant allele (CYP2C19*17) exists that is associated with increased transcription and thus higher CYP2C19 expression and even higher functional activity than that of the wild type CYP2C19-carrying EMs. Individuals carrying this CYP2C19*17 allele exhibit higher metabolic activation of prodrugs such as the breast cancer drug tamoxifen, the antimalarial chlorproguanil, and the antiplatelet drug clopidogrel. The former event is associated with a lower risk of breast cancer relapse, and the latter event with an increased risk of bleeding. Carriers of the CYP2C19*17 allele are also known to enhance the metabolism and thus the elimination of drugs such as the antidepressants escitalopram and imipramine, as well as the antifungal voriconazole. This consequently impairs the therapeutic efficacy of these drugs, thus requiring clinical dosage adjustments.
The third relatively well-characterized genetic polymorphism is that of CYP2C9. Two well-characterized variants of this enzyme exist, each with amino acid mutations that result in altered metabolism. The CYP2C9*2 allele encodes an Arg144Cys mutation, exhibiting impaired functional interactions with POR. The other allelic variant, CYP2C9*3, encodes an enzyme with an Ile359Leu mutation that has lowered affinity for many substrates. For example, individuals displaying the CYP2C9*3 phenotype have greatly reduced tolerance for the anticoagulant warfarin. The warfarin clearance in CYP2C9*3-homozygous individuals is about 10% of normal values, and these people have a much lower tolerance for the drug than those who are homozygous for the normal wild type allele. These individuals also have a much higher risk of adverse effects with warfarin (eg, bleeding) and with other CYP2C9 substrates such as phenytoin, losartan, tolbutamide, and some nonsteroidal anti-inflammatory drugs (Table 4–4). Note, however, that despite the predominant role of CYP2C9 in warfarin clearance (particularly that of its pharmacologically more potent S-isomer), warfarin maintenance doses are largely dictated by polymorphisms in the VKORC1 gene responsible for the expression of vitamin K epoxide reductase, the specific cellular target of warfarin, rather than by CYP2C9*2/*3 polymorphisms alone (see Chapter 5).
Allelic variants of CYP3A4 have also been reported, but their contribution to the well-known interindividual variability in drug metabolism apparently is limited. On the other hand, the expression of CYP3A5, another human liver isoform, is markedly polymorphic, ranging from 0% to 100% of the total hepatic CYP3A content. This CYP3A5 protein polymorphism is now known to result from a single nucleotide polymorphism (SNP) within intron 3, which enables normally spliced CYP3A5 transcripts in 5% of Caucasians, 29% of Japanese, 27% of Chinese, 30% of Koreans, and 73% of African Americans. Thus, it can significantly contribute to interindividual differences in the metabolism of preferential CYP3A5 substrates such as midazolam. Two other CYP3A5 allelic variants that result in a PM phenotype are also known.
Polymorphisms in the CYP2A6 gene have also been recently characterized, and their prevalence is apparently racially linked. CYP2A6 is responsible for nicotine oxidation, and tobacco smokers with low CYP2A6 activity consume less and have a lower incidence of lung cancer. CYP2A6 1B allelic variants associated with faster rates of nicotine metabolism have been recently discovered. It remains to be determined whether patients with these faster variants will fall into the converse paradigm of increased smoking behavior and lung cancer incidence.
Additional genetic polymorphisms in drug metabolism are being discovered. Of these, the gene for CYP2B6 has become noteworthy as one of the most polymorphic P450 genes, with a 20- to 250-fold variation in interindividual CYP2B6 expression. Despite its low (1–5%) contribution to the total liver P450 content, these CYP2B6 polymorphisms may have a significant impact on the CYP2B6-dependent metabolism of several clinically relevant drugs such as cyclophosphamide, S-methadone, efavirenz, nevirapine, bupropion, selegiline, and propofol. Of clinical relevance, women (particularly Hispanic-American women) express considerably higher hepatic levels of CYP2B6 protein than men.
Studies of theophylline metabolism in monozygotic and dizygotic twins that included pedigree analysis of various families have revealed that a distinct polymorphism may exist for this drug and may be inherited as a recessive genetic trait. Genetic drug metabolism polymorphisms also appear to occur for aminopyrine and carbocysteine oxidations. Regularly updated information on human P450 polymorphisms is available at http://www.cypalleles.ki.se/.
Although genetic polymorphisms in drug oxidations often involve specific P450 enzymes, such genetic variations can also occur in other enzymes. Recently, genetic polymorphisms in POR, the essential P450 electron donor, have been reported. In particular, an allelic variant (at a 28% frequency) encoding a POR A503V mutation has been reported to result in impaired CYP17-dependent sex steroid synthesis and impaired CYP3A4- and CYP2D6-dependent drug metabolism in vitro. Its involvement in clinically relevant drug metabolism, while predictable, remains to be established. Descriptions of a polymorphism in the oxidation of trimethylamine, believed to be metabolized largely by the flavin monooxygenase (Ziegler’s enzyme), result in the “fish-odor syndrome” in slow metabolizers, thus suggesting that genetic variants of other non-P450-dependent oxidative enzymes may also contribute to such polymorphisms.
B. Phase II Enzyme Polymorphisms
Succinylcholine is metabolized only half as rapidly in persons with genetically determined deficiency in pseudocholinesterase (now generally referred to as butyrylcholinesterase [BCHE]) as in persons with normally functioning enzyme. Different mutations, inherited as autosomal recessive traits, account for the enzyme deficiency. Deficient individuals treated with succinylcholine as a surgical muscle relaxant may become susceptible to prolonged respiratory paralysis (succinylcholine apnea). Similar pharmacogenetic differences are seen in the acetylation of isoniazid. The defect in slow acetylators (of isoniazid and similar amines) appears to be caused by the synthesis of less of the NAT2 enzyme rather than of an abnormal form of it. Inherited as an autosomal recessive trait, the slow acetylator phenotype occurs in about 50% of blacks and whites in the USA, more frequently in Europeans living in high northern latitudes, and much less commonly in Asians and Inuit (Eskimos). The slow acetylator phenotype is also associated with a higher incidence of isoniazid-induced peripheral neuritis, drug-induced autoimmune disorders, and bicyclic aromatic amine-induced bladder cancer.
A clinically important polymorphism of the TPMT (thiopurine S-methyltransferase) gene is encountered in Europeans (frequency, 1:300), resulting in a rapidly degraded mutant enzyme and consequently deficient S-methylation of aromatic and heterocyclic sulfhydryl compounds including the anti-cancer thiopurine drugs 6-mercaptopurine, thioguanine, and azathioprine, required for their detoxification. Patients inheriting this polymorphism as an autosomal recessive trait are at high risk of thiopurine drug-induced fatal hematopoietic toxicity.
Genetic polymorphisms in the expression of other phase II enzymes (UGTs and GSTs) also occur. Thus, UGT polymorphisms (UGT1A1*28) are associated with hyperbilirubinemic diseases (Gilbert’s syndrome) as well as toxic effects due to impaired drug conjugation and/or elimination (eg, the anticancer drug irinotecan). Similarly, genetic polymorphisms (GSTM1) in GST (mu1 isoform) expression can lead to significant adverse effects and toxicities of drugs dependent on its GSH conjugation for elimination.
C. Role of Pharmacogenomic Testing in Clinically Safe & Effective Drug Therapy
Despite our improved understanding of the molecular basis of pharmacogenetic defects in drug-metabolizing enzymes, their impact on drug therapy and ADRs, and the availability of validated pharmacogenetic biomarkers to identify patients at risk, this clinically relevant information has not been effectively translated to patient care. Thus, the much-heralded potential for personalized medicine, except in a few instances of drugs with a relatively low therapeutic index (eg, warfarin), has remained largely unrealized. This is so even though 98% of US physicians are apparently aware that such genetic information may significantly influence therapy. This is partly due to the lack of adequate training in translating this knowledge to medical practice, and partly due to the logistics of genetic testing and the issue of cost-effectiveness. Severe ADRs are known to contribute to 100,000 annual US deaths, about 7% of all hospital admissions, and an increased average length of hospital stay. Genotype information could greatly enhance safe and efficacious clinical therapy through dose adjustment or alternative drug therapy, thereby curbing much of the rising ADR incidence and its associated costs. (See Chapter 5 for further discussion.)
It is increasingly recognized that the human gut microbiome can also significantly influence drug responses. It thus serves as another relevant source of therapeutic misadventures and adverse drug-drug interactions. More than 1000 species of intestinal microorganisms have been identified, including obligate anaerobic bacteria and various yeasts that coexist in a dynamic, often symbiotic, ecological equilibrium. Their biotransformation repertoire is nonoxidative, albeit highly versatile, extending from predominantly reductive and hydrolytic reactions to decarboxylation, dehydroxylation, dealkylation, dehalogenation, and deamination. Notably, such bacterially mediated reduction of the cardiac drug digoxin significantly contributes to its metabolism and elimination. Co-treatment with antibiotics such as erythromycin or tetracycline increases digoxin serum levels twofold, increasing the risk of cardiotoxicity. Similarly, drugs that are primarily glucuronidated in the liver are excreted into the gut via the bile, whereupon they are subjected to de-glucuronidation by gut microbial β-glucuronidases (hydrolases). The pharmacologically active parent aglycone is subsequently reabsorbed into the portal circulation with consequent extension of its pharmacologic action and hepatic phase II reconjugation and subsequent enterohepatic recycling. Thus, if the parent drug is dosage limited or has a low therapeutic index, this may mean increased toxicity. For example, under normal dosage, the analgesic acetaminophen is largely metabolized via glucuronidation and sulfation, as discussed earlier, and eliminated into the hepatic sinusoidal plasma. However, upon overdosage, the increased production of these metabolites is quite likely to saturate their normal excretory transport process. Their consequently enhanced biliary excretion would subject a greater fraction of the acetaminophen-glucuronide to de-glucuronidation by intestinal microbial β-glucuronidases, which may further contribute to the toxic acetaminophen burden. This possibility is even more relevant for glucuronides of parent drugs of noted gastrointestinal toxicity. Accordingly, selective inhibition of microbial β-glucuronidases has been documented to alleviate the gastrointestinal toxicity of anticancer drugs such as irinotecan, as well as the enteropathies induced by nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, ketoprofen or diclofenac, that incur substantial enterohepatic circulation. This possibility has fueled the pharmaceutical design and development of even more selective inhibitors targeted against microbial β-glucuronidases.
Diet & Environmental Factors
Diet and environmental factors contribute to individual variations in drug metabolism. Charcoal-broiled foods and cruciferous vegetables are known to induce CYP1A enzymes, whereas grapefruit juice is known to inhibit the CYP3A metabolism of co-administered drug substrates (Table 4–2; also see below). Cigarette smokers metabolize some drugs more rapidly than nonsmokers because of enzyme induction (see previous section). Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than unexposed individuals. Such differences make it difficult to determine effective and safe doses of drugs that have narrow therapeutic indices.
Increased susceptibility to the pharmacologic or toxic activity of drugs has been reported in very young and very old patients compared with young adults (see Chapters 59 and 60). Although this may reflect differences in absorption, distribution, and excretion, differences in drug metabolism also play a role. Slower metabolism could be due to reduced activity of metabolic enzymes or reduced availability of essential endogenous cofactors.
Sex-dependent variations in drug metabolism have been well documented in rats but not in other rodents. Young adult male rats metabolize drugs much faster than mature female rats or prepubertal male rats. These differences in drug metabolism have been clearly associated with androgenic hormones. Clinical reports suggest that similar sex-dependent differences in drug metabolism also exist in humans for ethanol, propranolol, some benzodiazepines, estrogens, and salicylates.
Drug-Drug Interactions (DDIs) During Metabolism
Many substrates, by virtue of their relatively high lipophilicity, are not only retained at the active site of the enzyme but remain nonspecifically bound to the lipid endoplasmic reticulum membrane. In this state, they may induce microsomal enzymes, particularly after repeated use. Acutely, depending on the residual drug levels at the active site, they also may competitively inhibit metabolism of a simultaneously administered drug.
Enzyme-inducing drugs include various sedative-hypnotics, antipsychotics, anticonvulsants, the antitubercular drug rifampin, and insecticides (Table 4–5). Patients who routinely ingest barbiturates, other sedative-hypnotics, or certain antipsychotic drugs may require considerably higher doses of warfarin to maintain a therapeutic effect. On the other hand, discontinuance of the sedative inducer may result in reduced metabolism of the anticoagulant and bleeding—a toxic effect of the ensuing enhanced plasma levels of the anticoagulant. Similar interactions have been observed in individuals receiving various combinations of drug regimens such as rifampin, antipsychotics, or sedatives with contraceptive agents, sedatives with anticonvulsant drugs, and even alcohol with hypoglycemic drugs (tolbutamide). One inducer of note is St. John’s wort, a popular over-the-counter herbal medicine ingested as treatment for mild to severe depression. Because of its marked induction of hepatic CYP3A4 and, to a lesser extent, CYP2C9 and CYP2C19, St. John’s wort has been linked to a large number of DDIs. Most of such DDIs stem from P450 induction by St. John’s wort and entail accelerated P450-dependent metabolism of the co-ingested drug (eg, alprazolam, contraceptive estrogens, warfarin, lovastatin, delavirdine, ritonavir). In contrast, St. John’s wort-mediated CYP2C19 induction may enhance the activation of the antiplatelet prodrug clopidogrel by accelerating its conversion to the active metabolite. Finally, some St. John’s wort-elicited DDIs may entail decreased P450-dependent metabolism due to competitive inhibition and consequently increased plasma levels and clinical effect (eg, meperidine, hydrocodone, morphine, oxycodone). Other DDIs entail synergistic increases in serotonin levels (due to monoamine oxidase inhibition) and correspondingly increased serotonergic tone and adverse effects (eg, paroxetine, sertraline, fluoxetine, fenfluramine).
TABLE 4–5Partial list of drugs that enhance drug metabolism in humans. ||Download (.pdf) TABLE 4–5 Partial list of drugs that enhance drug metabolism in humans.
|Inducer ||Drugs Whose Metabolism Is Enhanced |
|Benzo[a]pyrene ||Theophylline |
|Carbamazepine ||Carbamazepine, clonazepam, itraconazole |
|Chlorcyclizine ||Steroid hormones |
|Ethchlorvynol ||Warfarin |
|Glutethimide ||Antipyrine, glutethimide, warfarin |
|Griseofulvin ||Warfarin |
|Phenobarbital and other barbiturates1 ||Barbiturates, chloramphenicol, chlorpromazine, cortisol, coumarin anticoagulants, desmethyl imipramine, digitoxin, doxorubicin, estradiol, itraconazole, phenylbutazone, phenytoin, quinine, testosterone |
|Phenylbutazone ||Aminopyrine, cortisol, digitoxin |
|Phenytoin ||Cortisol, dexamethasone, digitoxin, itraconazole, theophylline |
|Rifampin ||Coumarin anticoagulants, digitoxin, glucocorticoids, itraconazole, methadone, metoprolol, oral contraceptives, prednisone, propranolol, quinidine, saquinavir |
|Ritonavir2 ||Midazolam |
|St. John’s wort3 ||Alprazolam, cyclosporine, digoxin, indinavir, oral contraceptives, ritonavir, simvastatin, tacrolimus, warfarin |
It must also be noted that an inducer may enhance not only the metabolism of other drugs but also its own metabolism. Thus, continued use of some drugs may result in a pharmacokinetic type of tolerance—progressively reduced therapeutic effectiveness due to enhancement of their own metabolism.
Conversely, simultaneous administration of two or more drugs may result in impaired elimination of the more slowly metabolized drug and prolongation or potentiation of its pharmacologic effects (Table 4–6). Both competitive substrate inhibition and irreversible substrate-mediated enzyme inactivation may augment plasma drug levels and lead to toxic effects from drugs with narrow therapeutic indices. Indeed, such acute interactions of terfenadine (a second-generation antihistamine) with a CYP3A4 substrate-inhibitor (ketoconazole, erythromycin, or grapefruit juice) resulted in fatal cardiac arrhythmias (torsades de pointes) requiring its withdrawal from the market. Similar DDIs with CYP3A4 substrate-inhibitors (such as the antibiotics erythromycin and clarithromycin, the antidepressant nefazodone, the antifungals itraconazole and ketoconazole, and the HIV protease inhibitors indinavir and ritonavir) and consequent cardiotoxicity led to withdrawal or restricted use of the 5-HT4 agonist cisapride. Similarly, allopurinol both prolongs the duration and enhances the chemotherapeutic and toxic actions of mercaptopurine by competitive inhibition of xanthine oxidase. Consequently, to avoid bone marrow toxicity, the dose of mercaptopurine must be reduced in patients receiving allopurinol. Cimetidine, a drug used in the treatment of peptic ulcer, has been shown to potentiate the pharmacologic actions of anticoagulants and sedatives. The metabolism of the sedative chlordiazepoxide has been shown to be inhibited by 63% after a single dose of cimetidine; such effects are reversed within 48 hours after withdrawal of cimetidine.
TABLE 4–6Partial list of drugs that inhibit drug metabolism in humans. ||Download (.pdf) TABLE 4–6 Partial list of drugs that inhibit drug metabolism in humans.
|Inhibitor1 ||Drug Whose Metabolism Is Inhibited |
|Allopurinol, chloramphenicol, isoniazid ||Antipyrine, dicumarol, probenecid, tolbutamide |
|Chlorpromazine ||Propranolol |
|Cimetidine ||Chlordiazepoxide, diazepam, warfarin, others |
|Dicumarol ||Phenytoin |
|Diethylpentenamide ||Diethylpentenamide |
|Disulfiram ||Antipyrine, ethanol, phenytoin, warfarin |
|Ethanol ||Chlordiazepoxide (?), diazepam (?), methanol |
|Grapefruit juice2 ||Alprazolam, atorvastatin, cisapride, cyclosporine, midazolam, triazolam |
|Itraconazole ||Alfentanil, alprazolam, astemizole, atorvastatin, buspirone, cisapride, cyclosporine, delavirdine, diazepam, digoxin, felodipine, indinavir, loratadine, lovastatin, midazolam, nisoldipine, phenytoin, quinidine, ritonavir, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, triazolam, verapamil, warfarin |
|Ketoconazole ||Astemizole, cyclosporine, terfenadine |
|Nortriptyline ||Antipyrine |
|Oral contraceptives ||Antipyrine |
|Phenylbutazone ||Phenytoin, tolbutamide |
|Ritonavir ||Amiodarone, cisapride, itraconazole, midazolam, triazolam |
|Saquinavir ||Cisapride, ergot derivatives, midazolam, triazolam |
|Secobarbital ||Secobarbital |
|Spironolactone ||Digoxin |
|Troleandomycin ||Theophylline, methylprednisolone |
Impaired metabolism may also result if a simultaneously administered drug irreversibly inactivates a common metabolizing enzyme. These inhibitors, in the course of their metabolism by cytochrome P450, inactivate the enzyme and result in impairment of their own metabolism and that of other cosubstrates. This is the case of the furanocoumarins in grapefruit juice, eg, 6′,7′-dihydroxybergamottin and bergamottin, which inactivate CYP3A4 in the intestinal mucosa and consequently enhance its proteolytic degradation. This impairment of intestinal first-pass CYP3A4-dependent metabolism significantly enhances the bioavailability of drugs such as ergotamine, felodipine, nifedipine, terfenadine, verapamil, ethinylestradiol, lovastatin, saquinavir, and cyclosporine A and is associated with clinically relevant DDIs and food-drug interactions. The list of drugs subject to DDIs involving grapefruit juice is extensive and includes many drugs with a very narrow therapeutic index and a high potential for lethal adverse reactions. However, it must be borne in mind that not all commercially available grapefruit juices are equally potent, as the CYP3A4 inactivation potency is totally dependent on the amount of furanocoumarins extracted into the juice from the zest (highest), pith, and pulp of the grapefruit. Furthermore, recovery from these interactions is dependent on CYP3A4 resynthesis and thus may be slow.
Interactions between Drugs & Endogenous Compounds
Some drugs require conjugation with endogenous substrates such as GSH, glucuronic acid, or sulfate for their inactivation. Consequently, different drugs may compete for the same endogenous substrates, and the faster-reacting drug may effectively deplete endogenous substrate levels and impair the metabolism of the slower-reacting drug. If the latter has a steep dose-response curve or a narrow margin of safety, potentiation of its therapeutic and toxic effects may result.
Diseases Affecting Drug Metabolism
Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. Such conditions include alcoholic hepatitis, active or inactive alcoholic cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis, and acute viral or drug-induced hepatitis. Depending on their severity, these conditions may significantly impair hepatic drug-metabolizing enzymes, particularly microsomal oxidases, and thereby markedly affect drug elimination. For example, the half-lives of chlordiazepoxide and diazepam in patients with liver cirrhosis or acute viral hepatitis are greatly increased, with a corresponding increase in their effects. Consequently, these drugs may cause coma in patients with liver disease when given in ordinary doses.
Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4–7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. The impaired enzyme activity or defective formation of enzymes associated with heavy metal poisoning or porphyria also results in reduced hepatic drug metabolism. Pulmonary disease may also affect drug metabolism, as indicated by the impaired hydrolysis of procainamide and procaine in patients with chronic respiratory insufficiency and the increased half-life of antipyrine (a P450 functional probe) in patients with lung cancer.
TABLE 4–7Rapidly metabolized drugs whose hepatic clearance is blood flow-limited. ||Download (.pdf) TABLE 4–7 Rapidly metabolized drugs whose hepatic clearance is blood flow-limited.
Although the effects of endocrine dysfunction on drug metabolism have been well explored in experimental animal models, corresponding data for humans with endocrine disorders are scanty. Thyroid dysfunction has been associated with altered metabolism of some drugs and of some endogenous compounds as well. Hypothyroidism increases the half-life of antipyrine, digoxin, methimazole, and some β blockers, whereas hyperthyroidism has the opposite effect. A few clinical studies in diabetic patients indicate no apparent impairment of drug metabolism, although impairment has been noted in diabetic rats. Malfunctions of the pituitary, adrenal cortex, and gonads markedly reduce hepatic drug metabolism in rats. On the basis of these findings, it may be supposed that such disorders could significantly affect drug metabolism in humans. However, until sufficient evidence is obtained from clinical studies in patients, such extrapolations must be considered tentative.
Finally, the release of inflammatory mediators, cytokines, and nitric oxide associated with bacterial or viral infections, cancer, or inflammation are known to impair drug metabolism by inactivating P450s and enhancing their degradation.