Formation Of A Chemically Reactive Intermediate

For a number of drugs that undergo metabolism, CRM will be formed irrespective of the dose of the drug (Pirmohamed et al., 1996). When a drug is taken in therapeutic dosage, any toxic metabolite formed will be detoxified by normal enzymatic or non-enzymatic cellular defence mechanisms. An imbalance between bioactivation and bioinactiva-tion leading to toxicity may however be created by taking a drug overdose. This will lead to the formation of large amounts of chemically reactive metabolites, overwhelming the cellular detoxica-tion capacity, and leading to cell damage. The clearest example of this is paracetamol, which causes hepatotoxicity when taken in overdosage, and still causes about 160 deaths per year in the United Kingdom (Bray, 1993). According to the conventional definition of adverse drug reactions, paracetamol hepatotoxicity should not be classified as an adverse drug reaction, since the hepatic injury occurs when the drug is used inappropriately. However, it is important to note that the occurrence of liver damage with paracetamol and its severity is a function not only of the dose but also of various host factors (Pirmohamed et al., 1994). Indeed, paracetamol hepatotoxicity has been reported with therapeutic drug use. For example, a recent study in 67 alcoholics who had sustained liver injury after paracetamol ingestion showed that 40% had taken less than 4 g/day (the maximum recommended therapeutic dose) while another 20% had taken between 4 and 6 g/day (which is also regarded as a non-toxic dose) (Zimmerman and Maddrey, 1995).

In therapeutic dosage, paracetamol is largely metabolized by phase II processes (glucuronida-

tion and sulphation) to stable metabolites, but between 5% and 10% also undergoes P450 metabolism to the toxic N-acetyl p-benzoquino-neimine (NAPQI) metabolite (Nelson, 1990) (Figure 6.3). This is detoxified by cellular glutathione. In overdosage, saturation of the phase II metabolic pathways results in a greater proportion of the drug undergoing bioactivation. This ultimately leads to depletion of cellular glutathione, and allows the toxic metabolite to bind to hepatic proteins resulting in hepatocellular damage (Nelson, 1990). The use of N-acetylcysteine in the treatment of paracetamol overdosage illustrates the important point that elucidation of the mechanism of drug toxicity can lead to the development of rational therapies that will prevent the toxicity. Alcoholics show increased susceptibility to paracetamol overdosage because excess alcohol consumption results in depletion of glutathione (Lauterburg and Velez, 1988) and induction of the P450 isoform CYP2E1 (Raucy et al., 1989). Recent studies in knockout mice have shown that CYP2E1 is the primary isoform involved in the bioactivation of paracetamol (Lee et al., 1996).

Although experiments with transgenic mice have shown that in the absence of phase I oxidative pathways and therefore NAPQI formation, hepa-totoxicity does not occur, the precise pathway


Paracetamol detoxication

Glucuronyl transferases Sulphotransferases bioactivation

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