Variability of oral bioavailability for low dose methotrexate in rats.
The effects of food, antibiotics, diclofenac sodium (DS) and methotrexate (MTX) on oral bioavailability (BA) of MTX were examined in rats. Feeding didn't vary the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but enhanced those after oral dosing, and the oral BA. The twice daily oral doses of 40 mg/kg neomycin sulfate (NS) or mixed antibiotics (200 mg/kg NS + 200 mg/kg streptomycin sulfate + 200 mg/kg bacitracin) for 5 days didn't influence the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but induced the decreased Cmax and the delayed MRT after oral dosing. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats orally dosed with 1 or 5 mg/kg/day DS for 4 days were similar to those in the control rats, while the pre-treatment of 25 mg/kg/day DS delayed the elimination of MTX but didn't change the oral BA. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats, which received the intermittent oral doses of 7.5 mg/kg/3 doses/week MTX for 4 weeks, were comparable to those in the control rats, but the daily pre-treatment of 0.2 mg/kg/day MTX for 4 weeks increased the plasma concentrations after oral dosing, and the BA.
Kuroda
T
T
Department of Drug Metabolism, Medical Research Laboratories, Wyeth Lederle Japan, Ltd, Shiki-shi, Saitama.
Namba
K
K
Torimaru
T
T
Yamamoto
S
S
Akahori
M
M
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D004008:Diclofenac / Q000494:pharmacology; D005215:Fasting; D005746:Gastric Emptying / Q000187:drug effects; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D004008:Diclofenac; D008727:Methotrexate