Hepatic Drug Metabolism and Cytochrome P450

The liver is the principal site at which drugs and other foreign compounds are chemically transformed for elimination. This biotransformation is conventionally divided into Phase I reactions — dominated by the cytochrome P450 (CYP) superfamily — and Phase II conjugation reactions. Differences in CYP activity, whether genetic, induced, or inhibited, are a major source of the variability seen in how individuals respond to the same drug.

Definition

Hepatic drug metabolism is the enzymatic biotransformation of drugs and xenobiotics by the liver, predominantly through cytochrome P450-catalyzed Phase I reactions and subsequent Phase II conjugation, converting lipophilic compounds into more water-soluble forms for excretion.

Scope

The entry covers the two-phase scheme of biotransformation, the role of the cytochrome P450 enzymes (especially CYP3A4 and other major isoforms), first-pass metabolism, and the sources of inter-individual variability — pharmacogenetic polymorphism, enzyme induction and inhibition, and drug-drug interactions. It is a reference account of drug-metabolizing physiology and does not provide dosing or prescribing guidance.

Core questions

• What distinguishes Phase I from Phase II biotransformation?
• Which cytochrome P450 isoforms handle most drug metabolism?
• How do enzyme induction and inhibition produce drug-drug interactions?
• Why do genetic polymorphisms in CYP enzymes cause variable drug response?

Key concepts

• Phase I (oxidation, reduction, hydrolysis)
• Phase II (conjugation: glucuronidation, sulfation, acetylation)
• Cytochrome P450 superfamily
• CYP3A4 and other major isoforms
• First-pass (presystemic) metabolism
• Enzyme induction and inhibition
• Pharmacogenetic polymorphism
• Drug-drug interactions

Mechanisms

Lipophilic drugs are first made more reactive by Phase I reactions — principally oxidation catalyzed by membrane-bound cytochrome P450 enzymes of the hepatic endoplasmic reticulum — and then conjugated in Phase II to highly water-soluble groups for biliary or renal excretion (Wilkinson, 2005). A small number of CYP isoforms, with CYP3A4 metabolizing the largest share of clinically used drugs, account for most oxidative metabolism (Guengerich, 1999; Nelson et al., 2004). Because orally absorbed drugs traverse the gut wall and liver before reaching the systemic circulation, first-pass metabolism can substantially reduce the fraction of an oral dose that becomes systemically available. CYP activity varies between people through inherited polymorphisms and is modulated by other drugs and foods that induce or inhibit specific enzymes, which is the mechanistic basis of many drug-drug interactions and of pharmacogenetic differences in response (Evans & Relling, 1999).

Clinical relevance

Variation in hepatic drug metabolism helps explain why standard drug exposures differ between individuals and why some combinations of drugs interact. Understanding which enzymes metabolize a drug underpins pharmacogenomics and interaction prediction. This entry describes the underlying physiology and is not a source of dosing recommendations or individualized prescribing advice.

Evidence & guidelines

The biochemistry and clinical implications of hepatic drug metabolism are described in standard pharmacology reviews (Wilkinson, 2005; Guengerich, 1999), with CYP nomenclature standardized by Nelson and colleagues (2004) and the pharmacogenomic framework articulated by Evans and Relling (1999).

History

The cytochrome P450 pigment was identified in the late 1950s and 1960s and progressively resolved into a large gene superfamily, with a standardized nomenclature consolidated by Nelson and colleagues (2004). The recognition that polymorphisms in these enzymes underlie variable drug response gave rise to the field of pharmacogenetics and, later, pharmacogenomics (Evans & Relling, 1999).

Seminal works

• wilkinson-2005
• guengerich-1999
• evans-1999

Frequently asked questions

What is the difference between Phase I and Phase II metabolism?

Phase I reactions (mainly cytochrome P450-catalyzed oxidation) introduce or expose a reactive chemical group, while Phase II reactions attach a water-soluble molecule (such as glucuronic acid or sulfate) so the compound can be excreted.

Why does the same drug affect people differently?

Inherited differences in drug-metabolizing enzymes, plus induction or inhibition of those enzymes by other drugs and foods, change how fast a drug is cleared, producing different blood levels from the same dose.