Assessment of CYP2D6 and CY2C19 activity in vivo in humans: A cocktail study with dextromethorphan and chloroguanide alone and in combination

Objectives: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 and CYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan a nd chloroguanide/cycloguanil metabolic ratios, obtained after administratio n of the parent drugs either alone or in combination, are equivalent. Methods: Thirty-six healthy male volunteers received single oral doses of 8 0 mg dextromethorphan and 200 mg chloroguanide during a three-period, rando mized crossover study. Plasma and urine were collected to calculate metabol ic ratios and analyze the disposition kinetics of the probe drugs, Results: ALL subjects were extensive metabolizers for both CYP2D6 and CYP2C 19, Chloroguanide kinetics and urinary metabolic ratio were not altered aft er dextromethorphan administration. Dextromethorphan urinary metabolic rati o increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presenc e of chloroguanide, This was caused by an increase of dextromethorphan with out a significant change of dextrorphan in both urine and plasma, Inhibitio n of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphi nan did not appear to be responsible for this change because the log(dextro methorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration, The chloro guanide and dextromethorphan metabolic ratio determined from urine collecti on correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration, Conclusion: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CPP2C19 activit y can be determined from a blood sample drawn 3 hours after oral administra tion of dextromethorphan and chloroguanide, respectively.