Recent Developments in Hepatic Drug Oxidation Implications for Clinical Pharmacokinetics

Summary

Cytochrome P450 (P450) is the collective term for a group of related enzymes or isozymes which are responsible for the oxidation of numerous drugs and other foreign compounds, as well as many endogenous substrates including prostaglandins, fatty acids and steroids. Each P450 is encoded by a separate gene, and a classification system for the P450 gene superfamily has recently been proposed. The P450 genes are assigned to families and subfamilies according to the degree of similarity of the amino acid sequences of the protein part of the encoded P450 isozymes. It is estimated that there are between 20 and 200 different P450 genes in humans.

The human P450IID6 is a particular isozyme which has been extensively studied over the past 10 years. The P450IID6 is the target of the sparteine/debrisoquine drug oxidation polymorphism. Between 5 and 10% of Caucasians are poor metabolisers, and it has recently been shown that the P450IID6 enzyme is absent in the livers of these individuals. The defect has also been characterised at the DNA and messenger RNA (mRNA) level, and to date 3 different forms of incorrectly spliced P450IID6 pre-mRNAs have been identified in the livers of poor metabolisers.

The P450IID6 has a broad substrate specificity and is known to oxidise 15 to 20 commonly used drugs. The metabolism of these drugs is therefore subjected to the sparteine/debrisoquine oxidation polymorphism. The clinical significance of this polymorphism for a particular drug is defined according to the usefulness of phenotyping patients before treatment. It is concluded that this strategy would be of potential value for tricyclic antidepressants, some neuroleptics (e.g. perphenazine and thioridazine) and some antiarrhythmics (e.g. propafenone and flecainide).

The P450IID6 displays markedly stereoselective metabolism and appears uninducible by common inducers like rifampicin and Phenazone (antipyrine). With some substrates, such as Imipramine, desipramine and propafenone. P450IID6 becomes saturated at therapeutic doses. Finally, its function is potently inhibited by many commonly used drugs, for example, quinidine.

The most clinically relevant interaction in relation to P450IID6 function appears to be the potent inhibition by some neuroleptics of the metabolism of tricyclic antidepressants.

No drug-metabolising P450 has been so well characterised at the gene, protein and functional levels as the P4501ID6. This development is based on an extensive use of specific model drugs, the oxidation of which in vitro and in vivo is dependent on the function of P450IID6; it can be expected that other human drug-metabolising P450s will be similarly characterised in future.