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

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. 1987 Royal Pharmaceutical Society of Great Britain