Effects of aspirin and/or salicylate on hydrolysis and glucuronidation of indomethacin in rat erythrocytes and hepatocytes.
This study was conducted to explore the mechanism of the pharmacokinetic interaction between aspirin (ASP) and indomethacin (IND) using rat erythrocytes (RBCs) and hepatocytes. ASP was hydrolyzed to salicylic acid (SA) in both the RBCs and hepatocytes. Within RBCs, aspirin and/or salicylate (ASP/SA) increased the concentration of IND, accompanied by a constant hydrolysis of IND. In hepatocytes, a low dose of IND was subjected to glucuronidation rather than hydrolysis, and ASP/SA inhibited both the acylglucuronidation of IND and hydrolysis of IND glucuronide. A high dose of IND underwent hydrolysis with about double the glucuronidation, and ASP/SA decreased the ratio of hydrolysis to glucuronidation, accompanied by a loss of ASP, IND and their metabolites from the medium. Collectively, the results provide metabolic insight into the mechanism of drug-drug interaction between ASP/SA and IND in the hepatocytes and RBCs.
Department of Clinical Pharmacology and Toxicology, Showa Pharmaceutical University, Higashi-Tamagawagakuen, Machida, Tokyo, Japan.
Makiko
M
Shimizu
Aki
A
Tsuyuki
Chizuru
C
Yamamoto
Kumiko
K
Ohta
Reiko
R
Matsushita
Kayoko
K
Suzuki
Yoshiaki
Y
Matsumoto
Masamichi
M
Fukuoka
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001553:Benzbromarone / Q000097:blood; D043182:Carboxylesterase / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D004912:Erythrocytes / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007213:Indomethacin / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; D012459:Salicylates; D001553:Benzbromarone; D043182:Carboxylesterase; D001241:Aspirin; D007213:Indomethacin