PMID: 11920771Mar 29, 2002Paper

Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs

Journal of Pharmaceutical Sciences
Masanori KurohaEiichi Kokue

Abstract

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.

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Dec 18, 2001·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Masanori KurohaEiichi Kokue

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Citations

Sep 18, 2013·Drug Metabolism and Pharmacokinetics·Yoshihiro ShibataMasato Chiba
May 25, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·M IshizukaS Fujita
Sep 27, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S V MandlekarP H Marathe
Sep 14, 2007·Journal of Pharmaceutical Sciences·Hiroshi Komura, Masahiro Iwaki
Oct 24, 2009·Journal of Pharmaceutical Sciences·Stephan SchmidtHartmut Derendorf
Sep 21, 2006·The Veterinary Clinics of North America. Small Animal Practice·Lauren A Trepanier
May 7, 2010·Journal of Veterinary Pharmacology and Therapeutics·B KuKanich, M Hubin
Aug 11, 2015·Journal of Advanced Research·Kazuaki Sasaki, Minoru Shimoda
Jan 1, 2015·European Journal of Drug Metabolism and Pharmacokinetics·Jin-Seok ChoiDong-Hyun Choi
Oct 6, 2009·The Journal of Veterinary Medical Science·Syed Sher ShahMinoru Shimoda
Jul 6, 2014·PloS One·Antonella NapolitanoDerek J Nunez
Jul 14, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mosun A Ayan-OshodiStephen D Hall
Oct 6, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anooshirvan ShayeganpourDion R Brocks
May 1, 2021·Veterinary Sciences·Tussapon BoonyarattanasoonthornAnusak Kijtawornrat

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