Pharmacokinetics and Metabolism of MZPES, a Novel Lipophilic Antifolate

Abstract

m-Azidopyrimethamine ethanesulphonate salt (MZPES) is a new potent dihydrofolate reductase inhibitor designed to be both lipophilic and rapidly biodegradable. The drug is active against some methotrexate-refractory cell lines and against a broad spectrum of malignant cells in murine models. The pharmacokinetics of the drug were evaluated in the mouse, rat and man. A specific analytical method was developed to allow determination of MZP (the free base of MZPES) and its putative metabolite m-amino-pyrimethamine (MAP) in plasma, urine, faeces and tissues. Analytical methodology involved solvent extraction followed by reversed-phase ion-pair high pressure liquid chromatography. Mice were dosed at 10 and 20 mg/kg IP and 10 mg/kg PO. Absorption was rapid from both sites with a mean plasma elimination half-life of 4 hours. Oral bio-availability, relative to intraperitoneal injection, exceeded 95% in the mouse. MZP attained concentrations in mouse tissues 4 to 14 fold greater than those found in plasma and penetrated the blood-brain barrier effectively. Following intraperitoneal administration of MZP to the rat, the recovery of MZP and MAP in urine and faeces was 14% during 72 hours. MZPES was formulated for a phase I clinical evaluation as a 1% w/v aqueous solution and was administered by IV infusion in 5% dextrose over 1 hour. The drug obeyed 2-compartment kinetics with a central compartment volume of 27 litres and a volume of distribution of 118 litres. Plasma distribution and elimination half-lives were 0.27 and 34 hours respectively and plasma clearance was 7.5 L/hr. MZP was removed from plasma more rapidly than the prototypic lipophilic dihydrofolate reductase inhibitor metoprine (half-life 216 hours). The pharmacokinetics of MZPES showed no dose-dependency over the dose-range studied (27 to 460 mg/m2). The dose-limiting toxicity was nausea and vomiting. The short half-life of the drug should allow easy assessment of the optimum dose and schedule of administration.