Aims: Nine antimalarial (plus two metabolites of proguanil) and twelve non-antimalarial drugs were tested for their possible interaction with CYP3A4-catalysed 3-hydroxylation of quinine by human liver microsomes in vitro.
Methods: 3-Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective IC50 values were estimated for the twenty-one drugs and two metabolites of proguanil tested herein.
Results: Thirteen drugs exhibited an inhibitory effect on the 3-hydroxylation of quinine. According to the respective mean IC50 values, the inhibitory rank order of the drugs was: ketoconazole > troleandomycin (TAO, with preincubation) > doxycycline > omeprazole > primaquine > tetracycline = TAO (without preincubation) > nifedipine > erythromycin > verapamil > cimetidine > diltiazem > oleandomycin > hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean IC50 > 200 or 500 microM). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3-hydroxylation with a mean IC50 value of 17 microM, followed by primaquine and tetracycline, with mean IC50 values of 20 and 29 microM, respectively.
Conclusions: When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co-administrated with quinine.