Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole.
1. The inhibitory effects of cimetidine, nizatidine and omeprazole on the metabolic activity of CYP2C9, 2C19, 2D6 and 3A were investigated in human liver microsomes. Both cimetidine and omeprazole inhibited each of the CYP subfamily enzymes; in particular, omeprazole extensively inhibited the hydroxylation of S-mephenytoin (CYP2C19, Ki = 7.1 microM). Nizatidine exhibited no inhibition of any of the CYP isoforms examined. 2. Cimetidine inhibited the hydroxylation of tolbutamide but not of diclofenac, whereas omeprazole inhibited the hydroxylation of diclofenac but not that of tolbutamide. The ability to inhibit CYP2C9 varied with incubation time, as measured by the metabolic rate constant for the substrates. Therefore, suitable substrates and incubation times must be selected in inhibition studies examining metabolic clearance and the mechanism of inhibition of these drugs. 3. Nizatidine did not inhibit the metabolism of cisapride, glibenclamide, benidipine and simvastatin. Omeprazole inhibited the metabolism of cisapride (Ki = 0.4 microM), glibenclamide (11.7 microM) and benidipine (6.5 microM), whereas cimetidine inhibited the metabolism of glibenclamide (11.6 microM). To avoid drug-drug interactions, care needs to be taken to select suitable medicines for co-administration with anti-ulcer drugs.
Furuta
S
S
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd, Ohsato-gun, Saitama, Japan. ken-taisya@zeria.co.jp
Kamada
E
E
Suzuki
T
T
Sugimoto
T
T
Kawabata
Y
Y
Shinozaki
Y
Y
Sano
H
H
D000897:Anti-Ulcer Agents / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D016567:Nizatidine / Q000494:pharmacology*; D009853:Omeprazole / Q000494:pharmacology*; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D000897:Anti-Ulcer Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D002927:Cimetidine; D009853:Omeprazole; D016567:Nizatidine