Although the CYTP450 is by far the dominant enzymatic system involved in drug metabolism, it should be pointed out that other enzyme systems may undergo induction as well. We refer especially to some of the phase II metabolising enzymes, such as UDP-glucuronosyl transferase (UDPGT) and glutathione-S-transferase (GST). Naturally, since the phase II enzyme systems are involved in the major routes of detoxication, there is much interest in the induction of these systems, especially for cancer chemoprevention. In an attempt to localise the site of induction of drug metabolism, significant advances have been made in considering the role of the liver. As is already known, the major organ responsible for drug metabolism in most species (including man) is the liver. It then becomes evident that the main enzymatic system involved will be that of the cytochromes P450, the well-known family of oxidative hemoproteins responsible for a wide variety of oxidative transformations in a variety of organisms. The extent of induction of hepatic metabolism can reasonably be expected to be reflected in experimentally accessible indicators such as increased drug clearance, decreased drug plasma half-life, increased plasma bilirubin levels and others.

On the other hand, it should be borne in mind that the wide range of drugs and chemicals that act as inducers has been investigated for the most part on hepatocytes in vitro. Kinetic data obtained with isolated hepatocytes in vitro were then extrapolated to laboratory animals. However, although enzyme induction commonly results in increased rate of xenobiotic metabolism in vitro, the effects of enzyme induction may be dampened by physiological constraints in vivo. Furthermore, animal experiments can give only an indication of possible human response, necessitating very cautious extrapolation. One of the most common types of induction is that which is substrate-dependent. A well-known example of this phenomenon is the influence of phenobarbitone on the metabolism and duration of action of several drugs. Drugs affected include oral anticoagulants (anticoagulant effect decreased due to increased metabolism), tricyclic antidepressants (antidepressant effect decreased, by the same mechanism), corticosteroids (corticosteroid effect decreased, by the same mechanism), narcotics (increased CNS depression with meperidine, increased meperidine metabolites), theophyllines (theophylline effect decreased due to increased metabolism) and the muscle relaxant zoxazolamine (substantial metabolism increase, and consequently a significant decrease in the paralysis time)

Pre-treatment with phenobarbitone has also been shown to markedly increase the metabolism of felodipine and its pyridine analogue. Moreover, the inducing action of phenobarbitone may affect the expression of several specific CYP450 isoforms, as revealed in a recent study. The same phenomenon was observed even more recently in pregnant rat and foetal livers and placenta, impacting on different cytochrome P450 isoforms. From the above examples it is obvious that phenobarbitone induces the metabolism of different drugs, thus affecting the intensity and duration of their pharmacological action. The assumed molecular mechanism is a substantial increase in intranuclear RNAs that represent precursors to cytochrome P450 and mRNA. The immediate consequence will be a substantial increase in the hepatic levels of certain P450 isoforms, particularly CYP2B1and CYP2B2, with the former considered as the major phenobarbitone-inducible cytochrome P450.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access