Inhibition of metabolism of the 'nonclassical' antifolate, trimetrexate (2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline) by drugs containing an imidazole moiety

2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline (TMQ; NSC No. 249008) is a 'nonclassical' antifolate which is advocated as an alternative to methotrexate. TMQ is rapidly and extensively demethylated by a cytochrome P-450-mediated oxidation to a weakly cytotoxic compound of increased polarity. In this study, the effects of clinically used imidazole drugs ketoconazole, miconazole, clotrimazole, cimetidine, etintidine, clonidine and cibenzoline on the rat hepatic microsomal demethylation of TMQ in vitro was investigated. The nitrogen-substituted imidazole drugs (ketoconazole, miconazole, and clotrimazole) were potent non-competitive inhibitors of TMQ metabolism with IC50 values obtainable at therapeutic doses (less than 2 microM). Cimetidine and etintidine were comparatively weak, competitive inhibitors of TMQ metabolism (IC50 greater than 300 microM) and clonidine and cibenzoline were even less inhibitory (IC50 greater than 1 mM). The nitrogen-substituted imidazole drugs have the potential to dramatically alter the pharmacokinetic and pharmacodynamic profile of TMQ as well as other drugs in vivo.