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 AcetaminophenSome Trade Names GENAPAP TYLENOL VALORIN Click for Drug Monograph Caffeine ClarithromycinSome Trade Names BIAXIN Click for Drug Monograph EstradiolSome Trade Names ESTRADERM ESTROGEL VIVELLE Click for Drug Monograph HaloperidolSome Trade Names HALDOL Click for Drug Monograph LidocaineSome Trade Names XYLOCAINE Click for Drug Monograph MethadoneSome Trade Names DOLOPHINE Click for Drug Monograph OlanzapineSome Trade Names ZYPREXA Click for Drug Monograph PropranololSome Trade Names INDERAL Click for Drug Monograph RitonavirSome Trade Names NORVIR Click for Drug Monograph TacrineSome Trade Names COGNEX TheophyllineSome Trade Names ELIXOPHYLLIN THEO-DUR Click for Drug Monograph Tricyclic antidepressants VerapamilSome Trade Names CALAN ISOPTIN Click for Drug Monograph (R)-WarfarinSome Trade Names COUMADIN Click for Drug Monograph AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph CimetidineSome Trade Names TAGAMET Click for Drug Monograph CiprofloxacinSome Trade Names CILOXAN CIPRO Click for Drug Monograph ErythromycinSome Trade Names ERY-TAB ERYTHROCIN Click for Drug Monograph FluvoxamineSome Trade Names LUVOX Click for Drug Monograph TiclopidineSome Trade Names TICLID Click for Drug Monograph Charcoal-broiled beef Cigarette smoke OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph PhenytoinSome Trade Names DILANTIN Click for Drug Monograph PhenobarbitalSome Trade Names LUMINAL Click for Drug Monograph RifampinSome Trade Names RIFADIN RIMACTANE Click for Drug Monograph CYP2C9 CelecoxibSome Trade Names CELEBREX Click for Drug Monograph DiclofenacSome Trade Names CATAFLAM VOLTAREN Click for Drug Monograph FluoxetineSome Trade Names PROZAC SARAFEM Click for Drug Monograph GlipizideSome Trade Names GLUCOTROL Click for Drug Monograph GlyburideSome Trade Names DIABETA GLYNASE MICRONASE Click for Drug Monograph IndomethacinSome Trade Names INDOCIN Click for Drug Monograph NifedipineSome Trade Names ADALAT PROCARDIA Click for Drug Monograph PhenytoinSome Trade Names DILANTIN Click for Drug Monograph PiroxicamSome Trade Names FELDENE Click for Drug Monograph Progesterone TestosteroneSome Trade Names DELATESTRYL Click for Drug Monograph Tricyclic antidepressants ValproateSome Trade Names DEPAKENE Click for Drug Monograph (S)-WarfarinSome Trade Names COUMADIN Click for Drug Monograph AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph CimetidineSome Trade Names TAGAMET Click for Drug Monograph FluconazoleSome Trade Names DIFLUCAN Click for Drug Monograph LovastatinSome Trade Names ALTOPREV MEVACOR Click for Drug Monograph RitonavirSome Trade Names NORVIR Click for Drug Monograph SertralineSome Trade Names ZOLOFT Click for Drug Monograph Sulfamethoxazole TopiramateSome Trade Names TOPAMAX Click for Drug Monograph TrimethoprimSome Trade Names PROLOPRIM TRIMPEX Click for Drug Monograph ZafirlukastSome Trade Names ACCOLATE Click for Drug Monograph DexamethasoneSome Trade Names DECADRON DEXASONE HEXADROL Click for Drug Monograph PhenobarbitalSome Trade Names LUMINAL Click for Drug Monograph Other barbiturates PhenytoinSome Trade Names DILANTIN Click for Drug Monograph RifampinSome Trade Names RIFADIN RIMACTANE Click for Drug Monograph CYP2C19 DiazepamSome Trade Names VALIUM Click for Drug Monograph (S)-Mephenytoin OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph PentamidineSome Trade Names NEBUPENT PENTAM 300 Click for Drug Monograph PropranololSome Trade Names INDERAL Click for Drug Monograph (R)-WarfarinSome Trade Names COUMADIN Click for Drug Monograph CimetidineSome Trade Names TAGAMET Click for Drug Monograph FluoxetineSome Trade Names PROZAC SARAFEM Click for Drug Monograph FluvoxamineSome Trade Names LUVOX Click for Drug Monograph KetoconazoleSome Trade Names NIZORAL Click for Drug Monograph LansoprazoleSome Trade Names PREVACID Click for Drug Monograph OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph ParoxetineSome Trade Names PAXIL Click for Drug Monograph TiclopidineSome Trade Names TICLID Click for Drug Monograph CarbamazepineSome Trade Names TEGRETOL Click for Drug Monograph PhenobarbitalSome Trade Names LUMINAL Click for Drug Monograph PrednisoneSome Trade Names DELTASONE Click for Drug Monograph RifampinSome Trade Names RIFADIN RIMACTANE Click for Drug Monograph CYP2D6 β-Blockers CodeineSome Trade Names No US trade name Click for Drug Monograph DextromethorphanSome Trade Names BENYLIN DM DELSYM DEXALONE Click for Drug Monograph FlecainideSome Trade Names TAMBOCOR Click for Drug Monograph HaloperidolSome Trade Names HALDOL Click for Drug Monograph LidocaineSome Trade Names XYLOCAINE Click for Drug Monograph MexiletineSome Trade Names MEXITIL Click for Drug Monograph MorphineSome Trade Names DURAMORPH MS CONTIN MSIR ROXANOL Click for Drug Monograph OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph Phenothiazines QuinidineSome Trade Names CARDIOQUIN QUINAGLUTE Click for Drug Monograph RisperidoneSome Trade Names RISPERDAL Click for Drug Monograph SSRIs TamoxifenSome Trade Names NOLVADEX Click for Drug Monograph TestosteroneSome Trade Names DELATESTRYL Click for Drug Monograph TramadolSome Trade Names ULTRAM Click for Drug Monograph TrazodoneSome Trade Names DESYREL Click for Drug Monograph Tricyclic antidepressants VenlafaxineSome Trade Names EFFEXOR Click for Drug Monograph AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph BupropionSome Trade Names WELLBUTRIN ZYBAN Click for Drug Monograph CelecoxibSome Trade Names CELEBREX Click for Drug Monograph CimetidineSome Trade Names TAGAMET Click for Drug Monograph FluoxetineSome Trade Names PROZAC SARAFEM Click for Drug Monograph FluvoxamineSome Trade Names LUVOX Click for Drug Monograph MetoclopramideSome Trade Names REGLAN Click for Drug Monograph MethadoneSome Trade Names DOLOPHINE Click for Drug Monograph ParoxetineSome Trade Names PAXIL Click for Drug Monograph QuinidineSome Trade Names CARDIOQUIN QUINAGLUTE Click for Drug Monograph RitonavirSome Trade Names NORVIR Click for Drug Monograph SertralineSome Trade Names ZOLOFT Click for Drug Monograph CarbamazepineSome Trade Names TEGRETOL Click for Drug Monograph DexamethasoneSome Trade Names DECADRON DEXASONE HEXADROL Click for Drug Monograph RifampinSome Trade Names RIFADIN RIMACTANE Click for Drug Monograph PhenobarbitalSome Trade Names LUMINAL Click for Drug Monograph PhenytoinSome Trade Names DILANTIN Click for Drug Monograph CYP2E1 AcetaminophenSome Trade Names GENAPAP TYLENOL VALORIN Click for Drug Monograph Alcohol DisulfiramSome Trade Names ANTABUSE Click for Drug Monograph Alcohol IsoniazidSome Trade Names INH NYDRAZID Click for Drug Monograph CYP3A4 AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph Azole antifungals Benzodiazepines Ca channel blockers Caffeine CarbamazepineSome Trade Names TEGRETOL Click for Drug Monograph ClarithromycinSome Trade Names BIAXIN Click for Drug Monograph CyclosporineSome Trade Names NEORAL SANDIMMUNE Click for Drug Monograph DelavirdineSome Trade Names RESCRIPTOR Click for Drug Monograph EnalaprilSome Trade Names VASOTEC Click for Drug Monograph EstradiolSome Trade Names ESTRADERM ESTROGEL VIVELLE Click for Drug Monograph Estrogen ErythromycinSome Trade Names ERY-TAB ERYTHROCIN Click for Drug Monograph FentanylSome Trade Names ACTIQ DURAGESIC SUBLIMAZE Click for Drug Monograph FinasterideSome Trade Names PROPECIA PROSCAR Click for Drug Monograph IndinavirSome Trade Names CRIXIVAN Click for Drug Monograph LidocaineSome Trade Names XYLOCAINE Click for Drug Monograph Lopinavir Loratidine MethadoneSome Trade Names DOLOPHINE Click for Drug Monograph NelfinavirSome Trade Names VIRACEPT Click for Drug Monograph OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph PrednisoneSome Trade Names DELTASONE Click for Drug Monograph Progesterone RitonavirSome Trade Names NORVIR Click for Drug Monograph SaquinavirSome Trade Names FORTOVASE INVIRASE Click for Drug Monograph SildenafilSome Trade Names VIAGRA Click for Drug Monograph SirolimusSome Trade Names RAPAMUNE Click for Drug Monograph Statins TacrolimusSome Trade Names PROGRAF Click for Drug Monograph TamoxifenSome Trade Names NOLVADEX Click for Drug Monograph (R)-WarfarinSome Trade Names COUMADIN Click for Drug Monograph AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph AmprenavirSome Trade Names AGENERASE AtazanavirSome Trade Names REYATAZ Click for Drug Monograph Azole antifungals CimetidineSome Trade Names TAGAMET Click for Drug Monograph CiprofloxacinSome Trade Names CILOXAN CIPRO Click for Drug Monograph ClarithromycinSome Trade Names BIAXIN Click for Drug Monograph DelavirdineSome Trade Names RESCRIPTOR Click for Drug Monograph DiltiazemSome Trade Names CARDIZEM CARTIA DILACOR Click for Drug Monograph ErythromycinSome Trade Names ERY-TAB ERYTHROCIN Click for Drug Monograph FluoxetineSome Trade Names PROZAC SARAFEM Click for Drug Monograph FluvoxamineSome Trade Names LUVOX Click for Drug Monograph Grapefruit juice IndinavirSome Trade Names CRIXIVAN Click for Drug Monograph MetronidazoleSome Trade Names FLAGYL Click for Drug Monograph NefazodoneSome Trade Names SERZONE Click for Drug Monograph NelfinavirSome Trade Names VIRACEPT Click for Drug Monograph NifedipineSome Trade Names ADALAT PROCARDIA Click for Drug Monograph OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph ParoxetineSome Trade Names PAXIL Click for Drug Monograph PropoxypheneSome Trade Names DARVON DOLENE RitonavirSome Trade Names NORVIR Click for Drug Monograph SaquinavirSome Trade Names FORTOVASE INVIRASE Click for Drug Monograph SertralineSome Trade Names ZOLOFT Click for Drug Monograph VerapamilSome Trade Names CALAN ISOPTIN Click for Drug Monograph CarbamazepineSome Trade Names TEGRETOL Click for Drug Monograph DexamethasoneSome Trade Names DECADRON DEXASONE HEXADROL Click for Drug Monograph IsoniazidSome Trade Names INH NYDRAZID Click for Drug Monograph PhenobarbitalSome Trade Names LUMINAL Click for Drug Monograph PhenytoinSome Trade Names DILANTIN Click for Drug Monograph PrednisoneSome Trade Names DELTASONE Click for Drug Monograph RifampinSome Trade Names RIFADIN RIMACTANE Click for Drug Monograph

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 chloramphenicolSome Trade Names
CHLOROMYCETIN
Click for Drug Monograph
).

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

Content last modified July 2012