Investigation of xenobiotic metabolism by CYP2D6 and CYP2C19: importance of enantioselective analytical methods.
Investigations into the genetic polymorphism of drug metabolism have involved specific models to screen poor and extensive metabolisers of xenobiotics. Debrisoquine, sparteine, S-mephenytoin and dextromethorphan are particularly well known. They have been extensively described in the literature and are used to phenotype human subjects before performing 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 of cytochrome P-450. In many drugs, the hepatic microsomal oxidative metabolism involving stereogenic centres congregates either with CYP2D6 or with CYP2C19 or, in certain cases, with both of them. The availability of both CYP2D6 from poor and extensive metabolisers and an enantioselective assay would allow genetic polymorphism in drug biotransformation to be investigated in vitro ex vivo at an early stage of drug development before the IND (investigational new drug). Single-dose investigations in vivo can also be performed when only minimal pre-clinical toxicological data are available and produce more reliable results than in vitro studies. This paper focuses on the problem of genetic polymorphism in drug development and specifically discusses some relevant knowledge gained in the last two decades on enantioselective bioassays. Specific examples are given.
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I.P.A.S.S.A., Clinical Pharmacology Department, Stabio, Switzerland.
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D001189:Aryl Hydrocarbon Hydroxylases; D002845:Chromatography / Q000379:methods; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019075:Electrophoresis, Capillary; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6