The Role Of Drug Metabolism In Type B Adverse Drug Reactions

In general, drug metabolism can be considered to be a detoxication process in that it converts therapeutically active compounds to inactive metabolites, which can then be excreted harmlessly from the body. This process may require one or more than one drug metabolizing an enzyme which may be a phase I and/or phase II enzyme (Woolf and Jordan, 1987) (Figure 6.2). A drug may undergo sequential phase I and phase II metabolism, or alternatively, it may only undergo either phase I or phase II metabolism (Tephly and Burchell, 1990).

In certain circumstances, the drug-metabolizing enzymes can convert a drug to a toxic, chemically reactive metabolite (CRM), a process termed bioactivation (Pirmohamed et al., 1994, 1996) (Figure 6.2). Bioactivation may represent less than 1% of the overall metabolism of a drug. The body is equipped with formidable defence mechanisms, and in most cases the CRM will be detoxified (a process which can be termed bioinactivation)

Stable r metabolites I

Bioinactivation|

Detoxication

Cellular accumulation

Bioactivation

Chemically reactive metabolites

Toxicity

. Nucleic acid

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