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 all of the three substances and their metabolites in urine were investigated in 12 healthy subjects. The concentrations of parent drugs and main metabolites were measured in urine using modified HPLC-methods. All subjects were extensive metabolizers of mephenytoin and dextromethorphan as calculated using hydroxylation index (HI) for mephenytoin and as seen in the quantification of urinary dextromethorphan/dextrophan. A combined determination of coumarin and dextromethorphan with their metabolites or of coumarin and mephenytoin with their metabolites in urine is possible. The combined HPLC separation of all parent compounds and metabolites, however, is not useful because of the necessity to treat the urine samples in very different ways. An overlapping of retention times of the substances in HPLC does not occur. With it a simultaneous administration of all three drugs is possible. A following collection of urine over a period of 8-12 h serves for characterizing activities of different cytochrome P450 enzymes of patients. So particularly the influence of a long term drug therapy on the hydroxylation activities of these cytochromes is easily definable without the disturbing influence of intraindividual variation of drug oxidation with time.