Premium
Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes
Author(s) -
Zhao XueJun,
Ishizaki Takashi
Publication year - 1997
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1997.t01-1-00619.x
Subject(s) - quinine , pharmacology , primaquine , chemistry , proguanil , ketoconazole , drug interaction , microsome , doxycycline , chloroquine , pharmacokinetics , medicine , antibiotics , biochemistry , biology , in vitro , malaria , microbiology and biotechnology , immunology , antifungal
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 IC 50 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 IC 50 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 IC 50 >200 or 500 &mgr;m ). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3‐hydroxylation with a mean IC 50 value of 17 &mgr;m, followed by primaquine and tetracycline, with mean IC 50 values of 20 and 29 &mgr;m, 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.