The liver is the principal site of drug metabolism. Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even more so than the parent compound. An inactive or weakly active substance that has an active metabolite is called a prodrug, especially if designed to deliver the active moiety more effectively.

Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization; whatever the process, the goal is to make the drug easier to excrete. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Drug metabolism rates vary among patients. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached; in others, metabolism may be so slow that usual doses have toxic effects. Individual drug metabolism rates are influenced by genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions (especially those involving induction or inhibition of metabolism).

For many drugs, metabolism occurs in 2 phases. Phase I reactions involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis); these reactions are nonsynthetic. Phase II reactions involve conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine); these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and thus more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions; thus, phase numbers reflect functional rather than sequential classification.

Rate

For almost all drugs, the metabolism rate in any given pathway has an upper limit (capacity limitation). However, at therapeutic concentrations of most drugs, usually only a small fraction of the metabolizing enzyme's sites are occupied, and the metabolism rate increases with drug concentration. In such cases, called first-order elimination (or kinetics), the metabolism rate of the drug is a constant fraction of the drug remaining in the body (ie, the drug has a specific half-life). For example, if 500 mg is present in the body at time zero, after metabolism, 250 mg may be present at 1 h and 125 mg at 2 h (illustrating a half-life of 1 h). However, when most of the enzyme sites are occupied, metabolism occurs at its maximal rate and does not change in proportion to drug concentration; instead, a fixed amount of drug is metabolized per unit time (zero-order kinetics). In this case, if 500 mg is present in the body at time zero, after metabolism, 450 mg may be present at 1 h and 400 mg at 2 h (illustrating a maximal clearance of 50 mg/h and no specific half-life). As drug concentration increases, metabolism shifts from first-order to zero-order kinetics.

Cytochrome P-450

The most important enzyme system of phase I metabolism is cytochrome P-450 (CYP450), a microsomal superfamily of isoenzymes that catalyzes the oxidation of many drugs. The electrons are supplied by NADPH–CYP450 reductase, a flavoprotein that transfers electrons from NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) to CYP450. CYP450 enzymes can be induced or inhibited by many drugs and substances resulting in drug interactions in which one drug enhances the toxicity or reduces the therapeutic effect of another drug. For examples of drugs that interact with specific enzymes, see Pharmacokinetics: Common Substances That Interact With Cytochrome P-450 Enzymes  (see Factors Affecting Response to Drugs: Drug Interactions).

Table 2
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Common Substances That Interact With Cytochrome P-450 Enzymes  Enzyme Substrates Inhibitors Inducers CYP1A2 Acetaminophen Caffeine Clarithromycin Estradiol Haloperidol Lidocaine Methadone Olanzapine Propranolol Ritonavir Tacrine Theophylline Tricyclic antidepressants Verapamil (R)-Warfarin Amiodarone Cimetidine Ciprofloxacin Erythromycin Fluvoxamine Ticlopidine Charcoal-broiled beef Cigarette smoke Omeprazole Phenytoin Phenobarbital Rifampin CYP2C9 Celecoxib Diclofenac Fluoxetine Glipizide Glyburide Indomethacin Nifedipine Phenytoin Piroxicam Progesterone Testosterone Tricyclic antidepressants Valproate (S)-Warfarin Amiodarone Cimetidine Fluconazole Lovastatin Ritonavir Sertraline Sulfamethoxazole Topiramate Trimethoprim Zafirlukast Dexamethasone Phenobarbital Other barbiturates Phenytoin Rifampin CYP2C19 Diazepam (S)-Mephenytoin Omeprazole Pentamidine Propranolol (R)-Warfarin Cimetidine Fluoxetine Fluvoxamine Ketoconazole Lansoprazole Omeprazole Paroxetine Ticlopidine Carbamazepine Phenobarbital Prednisone Rifampin CYP2D6 β-Blockers Codeine Dextromethorphan Flecainide Haloperidol Lidocaine Mexiletine Morphine Omeprazole Phenothiazines Quinidine Risperidone SSRIs Tamoxifen Testosterone Tramadol Trazodone Tricyclic antidepressants Venlafaxine Amiodarone Bupropion Celecoxib Cimetidine Fluoxetine Fluvoxamine Metoclopramide Methadone Paroxetine Quinidine Ritonavir Sertraline Carbamazepine Dexamethasone Rifampin Phenobarbital Phenytoin CYP2E1 Acetaminophen Alcohol Disulfiram Alcohol Isoniazid CYP3A4 Amiodarone Azole antifungals Benzodiazepines Ca channel blockers Caffeine Carbamazepine Clarithromycin Cyclosporine Delavirdine Enalapril Estradiol Estrogen Erythromycin Fentanyl Finasteride Indinavir Lidocaine Lopinavir Loratidine Methadone Nelfinavir Omeprazole Prednisone Progesterone Ritonavir Saquinavir Sildenafil Sirolimus Statins Tacrolimus Tamoxifen (R)-Warfarin Amiodarone Amprenavir Atazanavir Azole antifungals Cimetidine Ciprofloxacin Clarithromycin Delavirdine Diltiazem Erythromycin Fluoxetine Fluvoxamine Grapefruit juice Indinavir Metronidazole Nefazodone Nelfinavir Nifedipine Omeprazole Paroxetine Propoxyphene Ritonavir Saquinavir Sertraline Verapamil Carbamazepine Dexamethasone Isoniazid Phenobarbital Phenytoin Prednisone Rifampin

With aging, the liver's capacity for metabolism through the CYP450 enzyme system is reduced by ≥ 30% because hepatic volume and blood flow are decreased. Thus, drugs that are metabolized through this system reach higher levels and have prolonged half-lives in the elderly (see Fig. 1: Pharmacokinetics: Comparison of pharmacokinetic outcomes for diazepam in a younger man (A) and an older man (B).). Because neonates have partially developed hepatic microsomal enzyme systems, they also have difficulty metabolizing many drugs.

Conjugation

Glucuronidation, the most common phase II reaction, is the only one that occurs in the liver microsomal enzyme system. Glucuronides are secreted in bile and eliminated in urine. Thus, conjugation makes most drugs more soluble and easily excreted by the kidneys. Amino acid conjugation with glutamine or glycine produces conjugates that are readily excreted in urine but not extensively secreted in bile. Aging does not affect glucuronidation. However, in neonates, conversion to glucuronide is slow, potentially resulting in serious effects (eg, as with chloramphenicol).

Conjugation may also occur through acetylation or sulfoconjugation. Sulfate esters are polar and readily excreted in urine. Aging does not affect these processes.

Last full review/revision July 2012 by Jennifer Le, PharmD, BCPS-ID