Effect of trimethoprim, paracetamol and cimetidine on trimetrexate metabolism by rat perfused isolated livers

Abstract

Trimetrexate (TMTX), a non-classical antifolate, is currently in clinical trial as an antineoplastic drug. In the rat perfused isolated liver, it undergoes extensive metabolism to two metabolites, M1 and M2, which are excreted primarily in the bile. The metabolites result from demethylation, and M1 is also glucuronidated. We examined the effects of three commonly used drugs on the elimination of 1 mg of TMTX by the rat perfused isolated liver (perfusate volume was 100 mL). Co-administration of either 1 or 5 mg cimetidine, a well-known inhibitor of microsomal oxidation, caused an increase in TMTX terminal elimination half-life (69 and 100% at 1 and 5 mg, respectively) and a decrease in clearance (40 and 46% at 1 and 5 mg, respectively). Paracetamol (acetaminophen) was chosen for a possible interaction with TMTX because its major metabolic pathway is glucuronidation. Five mg paracetamol resulted in no change in TMTX pharmacokinetics, but M1 concentrations were increased by 72% in bile, and M2 was not present in perfusate. The third drug tested was trimethoprim, which has some structural similarities to TMTX; however, no effects were noted on the levels of TMTX, M1 or M2 after 1 mg trimethoprim. These results indicate that TMTX elimination can be inhibited by cimetidine, probably due to competition for microsomal enzymes, and that paracetamol may alter the metabolite profiles; trimethoprim had no effect on TMTX disposition under the conditions employed.