A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition.
Our previous study showed that several drugs inhibited quinine 3-hydroxylation, a cytochrome P450 (CYP) 3A4-mediated reaction, in vitro. In this extended study, 13 drugs were selected and tested by human liver microsomes in order to further determine their respective inhibition constant (Ki) and type of inhibition. According to the apparent Ki values, the inhibitory rank order of these tested drugs was as follows: ketoconazole > doxycycline > omeprazole > tetracycline > troleandomycin (with pre-incubation) > primaquine > troleandomycin (without pre-incubation) > nifedipine > erythromycin > verapamil > oleandomycin > diltiazem > cimetidine > hydralazine. Among these drugs, doxycycline, tetracycline, ketoconazole, nifedipine and hydralazine were judged as mixed inhibitors; whereas, the remaining other drugs tested were judged as competitive inhibitors. When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, troleandomycin and erythromycin are likely to be inhibitors of quinine metabolism in patients when these drugs are co-administrated with quinine.
Zhao
X J
XJ
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo.
Ishizaki
T
T
D002121:Calcium Channel Blockers / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009853:Omeprazole / Q000494:pharmacology; D011803:Quinine / Q000493:pharmacokinetics*
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D011803:Quinine; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole