LACK OF PHARMACOKINETIC INTERACTION BETWEEN DEXTROMETHORPHAN, COUMARIN AND MEPHENYTOIN IN MAN AFTER SIMULTANEOUS ADMINISTRATION

The possible interference of simultaneously given dextromethorphan (10 mg dextromethorphan-HBr-H2O), coumarin (10 mg), and mephenytoin (100 mg (R/S)-mephenytoin) on oxidative routes of drug metabolism performed by different cytochrome P450 enzymes and the possibility to detect al l of the three substances and their metabolites in urine were investig ated in 12 healthy subjects. The concentrations of parent drugs and ma in metabolites were measured in urine using modified HPLC-methods. All subjects were extensive metabolizers of mephenytoin and dextromethorp han as calculated using hydroxylation index (HI) for mephenytoin and a s seen in the quantification of urinary dextromethorphan/dextrophan. A combined determination of coumarin and dextromethorphan with their me tabolites or of coumarin and mephenytoin with their metabolites in uri ne is possible. The combined HPLC separation of all parent compounds a nd metabolites, however, is not useful because of the necessity to tre at the urine samples in very different ways. An overlapping of retenti on times of the substances in HPLC does not occur. With it a simultane ous administration of all three drugs is possible. A following collect ion of urine over a period of 8-12 h serves for characterizing activit ies of different cytochrome P450 enzymes of patients. So particularly the influence of a long term drug therapy on the hydroxylation activit ies of these cytochromes is easily definable without the disturbing in fluence of intraindividual variation of drug oxidation with time.