title: Contribution of cytochrome P450 and UDT-glucuronosyltransferase to the metabolism of drugs containing carboxylic acid groups: risk assessment of acylglucuronides using human hepatocytes.
abstract: 1. In order to evaluate the inhibition activity of 1-aminobenzotriazole (ABT) and (-)-borneol (borneol) against cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), the substrates of these metabolic enzymes were incubated with ABT and borneol in human hepatocytes. We found that 3 mM ABT and 300 μM borneol were the most suitable experimental levels to specifically inhibit CYP and UGT. 2. Montelukast, mefenamic acid, flufenamic acid, diclofenac, tienilic acid, gemfibrozil, ibufenac and repaglinide were markedly metabolized in human hepatocytes, and the metabolism of gemfibrozil, mefenamic acid and flufenamic acid was inhibited by borneol. With regard to repaglinide, montelukast, diclofenac and tienilic acid, metabolism was inhibited by ABT. Ibufenac was partly inhibited by both inhibitors. Zomepirac, tolmetin, ibuprofen, indomethacin and levofloxacin were moderately metabolized by human hepatocytes, and the metabolism of zomepirac, ibuprofen and indomethacin was equally inhibited by both ABT and borneol. The metabolism of tolmetin was strongly inhibited by ABT, and was also inhibited weakly by borneol. Residual drugs, telmisartan, valsartan, furosemide, naproxen and probenecid were scarcely metabolized. 3. Although we attempted to predict the toxicological risks of drugs containing carboxylic groups from the combination chemical stability and CLint via UGT, the results indicated that this combination was not sufficient and that clinical daily dose is important.
authors.affiliation: Laboratory for Safety Assessment and ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation , Mifuku Izunokuni, Shizuoka , Japan and.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Jinno
authors.forename: Mizuka
authors.initials: M
authors.lastname: Tagashira
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsurui
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D001892:Camphanes / Q000494:pharmacology; D002264:Carboxylic Acids / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D012015:Reference Standards; D018570:Risk Assessment; D013379:Substrate Specificity / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001892:Camphanes; D002264:Carboxylic Acids; D020719:Glucuronides; D014230:Triazoles; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C022871:isoborneol
keywords: (−)-borneol; 1-aminobenzotriazole; UDP-glucuronosyltransferase; acylglucuronide; cytochrome P450; human hepatocyte