Evaluation of drug interactions in intact hepatocytes: Inhibitors of terfenadine metabolism

Toxicology in Vitro : an International Journal Published in Association with BIBRA
M Jurima-RometA P Li

Abstract

Terfenadine has been associated with several adverse drug interactions and it was of interest to develop in vitro systems to explain and predict such interactions. The metabolism of terfenadine was studied using intact hepatocytes from primary human and rat hepatocyte cultures, and the immortalized human hepatoma cell line HepG2. Rates and routes of biotransformation were analysed by HPLC. Terfenadine was extensively metabolized by all three cell culture systems during exposure periods ranging from 4 to 24 hr. Human and rat hepatocytes and HepG2 cells formed products of C-oxidation (an acid metabolite and its precursor alcohol metabolite). Human hepatocytes also formed the N-dealkylation product azacyclonol. Several cytochrome P4503A (CYP3A) substrates and inhibitors were evaluated for their ability to inhibit terfenadine biotransformation. In rat hepatocytes, ketoconazole, erythromycin and troleandomycin failed to inhibit; in HepG2 cells, only ketoconazole potently inhibited terfenadine metabolism. In human hepatocytes, ketoconazole, itraconazole, erythromycin, troleandomycin, cyclosporin and naringenin inhibited terfenadine metabolism. The results suggest that human hepatocytes may be a useful system for screening for inhibit...Continue Reading

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Citations

Jun 21, 2012·European Journal of Drug Metabolism and Pharmacokinetics·Mahmud KajbafStefano Fontana
Sep 2, 2009·Proceedings of the National Academy of Sciences of the United States of America·Srivatsan KidambiYaakov Nahmias
Aug 12, 1999·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·A G Renwick
May 13, 2006·The Journal of Pharmacology and Experimental Therapeutics·Ryan Z TurncliffKim L R Brouwer
Mar 21, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·James C FuscoeQiang Shi

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