Presystemic elimination of budesonide in man when administered locally at different levels in the gut, with and without local inhibition by ketoconazole

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
J SeidegårdO Borgå

Abstract

The CYP3A4 substrate budesonide was used to investigate gut wall first-pass metabolism in jejunum, ileum and colon of eight healthy men. Three milligram budesonide in solution was installed at each location by intubation, with or without immediate prior local administration of 16mg ketoconazole. Simultaneously, deuterium-labelled budesonide (0.2mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated using LC-MS/MS. Ketoconazole increased budesonide systemic availability significantly in jejunum (from 11.8 to 21.7%) and ileum (from 15.9 to 31.8%). T(max) and MAT were unaffected. No significant effects were noted after colon administrations, nor were there any effects on the pharmacokinetics of intravenously administered budesonide. The increased bioavailability is most probably explained as inhibition of gut wall metabolism. The data are in accordance with the well-known CYP3A activity in the small intestine, evidently capable of metabolising at least half the absorbed dose of budesonide. In contrast, the results indicate that this enzyme activity is insignificant in the colon.

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Citations

Dec 29, 2012·American Journal of Veterinary Research·Marco PietraPaola Roncada
Apr 28, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Janeric SeidegårdOlof Borgå
Jan 14, 2009·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Christian ZimmermannAlfred H Schinkel
Feb 12, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Christer TannergrenAnders Lindahl
Aug 10, 2016·Molecular Pharmaceutics·David DahlgrenHans Lennernäs
Apr 1, 2018·Journal of Gastroenterology and Hepatology·Stephan MiehlkeChris Probert
Nov 23, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Amol A RajeKasim A Mookhtiar
May 7, 2010·Clinical Pharmacology and Therapeutics·I B SkottheimR Sandbu
Nov 10, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Angela EffingerNikoletta Fotaki
Feb 22, 2021·Advanced Drug Delivery Reviews·Zahari VinarovPatrick Augustijns

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