Isotope effects on pathways of metabolism

Abstract

In recent studies (Horning et al., 1976) we have shown that the metabolism of a drug may be shifted by deuterium labelling if the drug is metabolised by multiple alternative pathways. Deuterated analogues of caffeine (1-trideuteromethyl3,7-dimethylxanthine and 7-trideuteromethyl-1,3-dimethylxanthine) and antipyrine (2-trideuteromethyl-3-methyl- and 2-methyl-3-trideuteromethyl1-phenyl-3-pyrazoline-5-one) were employed. The oxidation of the —CD₃ group was depressed and the metabolism was shifted to other pathways that did not involve cleavage of a carbon—deuterium bond. The change in metabolic pathways, like the primary isotope effect, occurs when deuterium is substituted at a principal site of metabolism and when oxidation is a primary mode of metabolism. However, this response, which we have observed in both in vivo and in vitro experiments, is different from the primary isotope effect, which is usually defined as the ratio of rate constants (k_H/k_D) or ratio of products formed [H]/[D]. For this reason we have used the term ‘metabolic switching’ to describe the effect of deuterium substitution on compounds that are metabolised by multiple alternative pathways rather than sequentially.