Dose-dependent Pharmacokinetics of Methotrexate and 7-Hydroxymethotrexate in the Rat in Vivo

摘要: The pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in bile, urine, serum was studied rats vivo after short-time infusions 10, 50, 250, 1000 mg/kg MTX. All animals were anesthetized drained bile during experiments. biliary secretion rate MTX approached saturation when levels surpassed 700-800 microM, causing a significant reduction recovery as the parent compound (49 to 32%) at doses exceeding 50 mg/kg. hepatic metabolism 7-hydroxy metabolite not saturated used. Serum demonstrated dose dependency, inasmuch 10 accompanied by reduced total body clearance (Clr) (ClB). A finding relation acute hepatotoxicity reported high-dose humans occurrence cholestasis 30-90 min drug infusion observation macroscopic precipitations duct five six treated with In these animals, cessation occurred similar 7-OH-MTX [9800 +/- 1100 (SD) microM], while single rat that secreted throughout experiment had 5-fold lower peak concentration bile. Analysis precipitates formed vitro found constitute 97% 3% content precipitated material.