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  • Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more water-soluble compounds.

  • Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities.

  • Phase I reactions involve hydrolysis, reduction, and oxidation. These reactions expose or introduce a functional group (—OH, —NH2, —SH, or —COOH), and usually result in only a small increase in hydrophilicity.

  • Phase II biotransformation reactions include glucuronidation, sulfonation (more commonly called sulfation), acetylation, methylation, and conjugation with glutathione (mercapturic acid synthesis), which usually result in increased hydrophilicity and elimination.

The overall fate or disposition of a xenobiotic, which encompasses its absorption, distribution, metabolism, and elimination or ADME, is determined by three major factors, namely, passive diffusion across biological membranes or between cells (i.e., transcellular and paracellular passive diffusion, respectively), facilitated transport by uptake and/or efflux transporters, and biotransformation (invariably called metabolism in the case of drugs) (Figs. 6–1 and 6–2). Biotransformation has been described as an enzymatic process of chemical modification that changes the physicochemical properties of a xenobiotic from those that favor absorption and distribution (i.e., high passive permeability associated with high lipophilicity) to those that favor elimination (i.e., low passive permeability associated with high hydrophilicity).


Role of passive diffusion, transport, and biotransformation in the disposition of a lipophilic acidic xenobiotic. OAT, organic anion transporter; OATP, organic anion transporting polypeptide; PPB, plasma protein binding; TPSA, topological polar surface area.


Role of passive diffusion, transport, and biotransformation in the disposition of a lipophilic basic xenobiotic. α1-AGP, α1-acid glycoprotein; AO, aldehyde oxidase; CYP, cytochrome P450; MAO, monoamine oxidase; NAT, N-acetyltransferase; PPB, plasma protein binding; TPSA, topological polar surface area; UGT, UDP-glucuronosyltransferase.

Biotransformation has traditionally been divided into two phases. Phase 1 biotransformation involves oxidation, reduction, and hydrolysis, which result in the introduction or exposure of functional groups such as –OH, –NH2, –SH, or –COOH. Phase 2 biotransformation involves conjugation of the xenobiotic or its Phase 1 metabolite(s) with an acid (glucuronic acid or sulfonic acid) or zwitterion (glutathione or amino acids such as glycine, taurine, and glutamine). Phase 1 biotransformation facilitates the elimination of xenobiotics by increasing their topological surface area (TPSA) and lowering their log P, both of which decrease membrane permeation by passive diffusion and decrease the likelihood of the excreted metabolites being reabsorbed from the small intestine or kidney. Phase 1 biotransformation also produces metabolites that potentially undergo Phase 2 biotransformation, which facilitates the elimination of xenobiotics by adding an ionizable group (often an acidic moiety that is predominantly [>99%] negatively charged above pH 7) that is associated with relatively large increases in TPSA and decreases in log P.

This chapter describes some fundamental principles of xenobiotic biotransformation, and describes the ...

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