Drug Metabolism
Two phases of drug metabolism are traditionally distinguished—phase I and phase II—which generally occur sequentially. Many drugs undergo both phase I and phase II, while others only undergo either phase I or phase II. Phase I is characterised by modification reactions, whereby the parent drug is modified by adding reactive and polar groups, resulting in a more hydrophilic compound; in some cases, a polar group is unmasked or revealed by drug metabolism. Phase II metabolism is characterised by conjugation. Metabolites resulting from phase I metabolism may be conjugated to even more polar, more readily excreted large compounds. This oversimplification of drug metabolism does not imply that only the parent compound itself is active and that metabolites are not. Some drugs are inactive and need to be metabolised to exert their effect, for example, carbamazepine, enalapril and oseltamivir. Other drugs may have metabolites with the same therapeutic effect as the parent compound, such as morphine and its metabolite morphine-6-glucuronide or venlafaxine and desvenlafaxine. Finally, some metabolites may be responsible for adverse drug reactions. For example, paracetamol is metabolised to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is associated with acute liver injury after overdoses.
Phase I Enzymes
The most abundant and best studied phase I system is the cytochrome P450 (CYP) superfamily of DMEs. It consists of at least 56 genes that code for functional enzymes. While most drugs are substrates for members of CYP1A, CYP2A-2E and CYP3A subfamilies, many endogenous compounds are substrates for the other subfamilies. More than half of all metabolised drugs are subject to CYP450-mediated metabolism (Table 1). Individual CYPs are named according to similarities in sequence and use the root symbol CYP for cytochrome P450. CYPs that share at least 40% sequence similarity are grouped into families denoted by an Arabic number after the CYP root. Subfamilies, designated by a letter, represent highly related genes (eg, CYP2C), while individual CYPs in a subfamily are numbered sequentially (eg, CYP3A4, CYP3A5). Other phase I DME families include the alcohol dehydrogenases (ADH), classes I–V. Ethanol is the best known substrate of ADH. The flavin-containing mono-oxygenase (FMO) protein family represents a group of enzymes that catalyse chemical reactions via the bound flavin-containing cofactors, of which FMO1, 2 and 3 are the enzymes active in drug metabolism. Voriconazole is an example of an FMO3 substrate, although phase I enzymes, such as CYP2C19, may be more important to its overall metabolism.
Phase II Enzymes
Different families of DMEs are responsible for phase II metabolism: for example, UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT), glutathione-S-transferases (GST), N-acetyltransferases (NAT), thiopurine S-methyltransferase (TPMT) (Table 1). Note that these families encompass multiple enzymes that are individually regulated (with the exception of TMPT, which is a single enzyme). This feature is often overlooked, especially for glucuronidation, as UGT1 and UGT2 are two distinct gene families with multiple enzymes. Hence, the disposition of a UGT1A1 substrate (ie, bilirubin) may not mirror the disposition of a UGT1A9 (eg, paracetamol) or UGT2B7 substrate (eg, morphine).