CHLOROQUINE MODULATION OF SPECIFIC METABOLIZING ENZYMES ACTIVITIES - INVESTIGATION WITH SELECTIVE 5 DRUG COCKTAIL

Aims The aim of this study was to investigate whether chloroquine can inhibit drug metabolism in humans, if such inhibition is general or se lective for certain enzymes and evaluate the potential for and clinica l significance of any drug-drug interactions when chloroquine is co-ad ministered with other drugs. Methods The study was conducted in fourte en normal non-smoking healthy male volunteers using a cocktail of five drugs consisting of caffeine, mephenytoin, debrisoquine, chlorzoxazon e and dapsone to assess activities of cytochromes P450 (CYP) 1A2, 2C19 , 2D6, 2E1 and 3A4 respectively. Dapsone was also used to assess N-ace tyltransferase activity. The activities were assessed at baseline, aft er one and seven daily doses (250 mg daily) of chloroquine and 7 and 1 4 days after stopping chloroquine dosing. Results Chloroquine caused a progressive and significant decrease in CYP2D6 activity as measured b y debrisoquine metabolism from first to seventh dose and the activity returned to baseline gradually over 14 days after stopping administrat ion. There was no effect on the metabolism of any of the other probe d rugs. Conclusions Chloroquine has been shown to be capable of inhibiti ng the activity of CYP2D6 in vivo in humans. This effect is selective as activities of other enzymes investigated were not affected. The eff ect was modest but suggests a potential for drug-drug interactions whe n co-administered with other drugs that are substrates for this enzyme . The clinical significance of such an interaction will depend on the therapeutic index of any drug involved.