INVESTIGATION OF XENOBIOTIC METABOLISM BY CYP2D6 AND CYP2C19 - IMPORTANCE OF ENANTIOSELECTIVE ANALYTICAL METHODS

Investigations into the genetic polymorphism of drug metabolism have i nvolved specific models to screen poor and extensive metabolisers of x enobiotics. Debrisoquine, sparteine, S-mephenytoin and dextromethorpha n are particularly well known. They have been extensively described in the literature and are used to phenotype human subjects before perfor ming investigations with new drugs which are believed to be under the control of a genetic polymorphism. Dextromethorphan, debrisoquine and sparteine are good substrates for CYP2D6, whereas the S-enantiomer of mephenytoin is a good substrate for CYP2C19, both being two isozymes o f cytochrome P-450, In many drugs, the hepatic microsomal oxidative me tabolism involving stereogenic centres congregates either with CYP2D6 or with CYP2C19 or, in certain cases, with both of them. The availabil ity of both CYP2D6 from poor and extensive metabolisers and an enantio selective assay would allow genetic polymorphism in drug biotransforma tion to be investigated in vitro ex vivo at an early stage of drug dev elopment before the IND (investigational new drug). Single-dose invest igations in vivo can also be performed when only minimal pre-clinical toxicological data are available and produce more reliable results tha n in vitro studies. This paper focuses on the problem of genetic polym orphism in drug development and specifically discusses some relevant k nowledge gained in the last two decades on enantioselective bioassays specific examples; are given.