PMID: 15228147Jul 2, 2004Paper

Transport proteins and intestinal metabolism: P-glycoprotein and cytochrome P4503A

Therapeutic Drug Monitoring
Uwe Christians

Abstract

Although traditionally the liver was considered the main site of pharmacokinetic drug interactions, this view has been reexamined in light of the finding that cytochrome P4503A4 (CYP3A) enzymes are expressed at high levels in mature villus tip enterocytes. Because of their topographic location in small intestinal enterocytes and their overlap in substrates, functional interactions between P-glycoprotein and CYP3A were suggested. Although the functional interaction between CYP3A and P-glycoprotein is not yet completely understood, experimental evidence suggests several mechanisms: (1) CYP3A and P-glycoprotein are coregulated via the orphan nuclear receptor SXR/PXR; (2) drugs are repeatedly taken up and pumped out of the enterocytes by P-glycoprotein, and repeated exposure to CYP3A enzymes increases the probability of a drug being metabolized; (3) P-glycoprotein keeps intracellular drug concentrations within the linear range of CYP3A enzymes; (4) metabolism results in better substrates for P-glycoprotein; and (5) metabolism shifts affinity to other intestinal efflux transporters to avoid competitive interaction of metabolites with P-glycoprotein-mediated efflux of the parent drug.

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Citations

Nov 16, 2007·Expert Opinion on Pharmacotherapy·Sarah M RobertsonAlice Pau
May 12, 2018·Lipids in Health and Disease·Jyothshna Devi KatamreddyJaya Preethi Peesa
Mar 11, 2005·Expert Opinion on Pharmacotherapy·Sarah M RobertsonAlice K Pau
May 21, 2005·Therapeutic Drug Monitoring·Ian S WestleyMaree J James
Nov 22, 2005·Expert Opinion on Drug Delivery·Suresh KatragaddaAshim K Mitra
May 13, 2009·American Journal of Therapeutics·Joseph Prandota
Jan 10, 2014·American Journal of Therapeutics·Ali Al-Khazaali, Rohit Arora
Feb 25, 2018·Pharmaceutical Research·Seyoum AyehunieMitchell Klausner
Jan 19, 2006·Therapeutic Drug Monitoring·Uwe ChristiansManuel Haschke
Mar 18, 2006·British Journal of Clinical Pharmacology·Sarah M RobertsonScott R Penzak
Jul 26, 2006·Expert Opinion on Drug Metabolism & Toxicology·Jill S Warrington, Leslie M Shaw
Dec 14, 2004·The Annals of Pharmacotherapy·Raymond G Morris
Aug 6, 2015·Transplantation·Felix KrenzienStefan G Tullius
Feb 20, 2010·Molecular Nutrition & Food Research·Maret G Traber
Jul 6, 2005·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Guido FillerUwe Christians
Jul 26, 2006·Expert Opinion on Drug Metabolism & Toxicology·Uwe ChristiansManuel Haschke
Jan 9, 2008·European Journal of Clinical Pharmacology·Shaojun ShiUlrich Klotz
May 30, 2008·Journal of Clinical Pharmacology·Yanfeng WangHorst Schran
Nov 25, 2016·Biomedical Reports·Adel AlkhedaideZein Shaban Ibrahim
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Sep 12, 2006·Free Radical Biology & Medicine·Debbie J MustacichMaret G Traber
Sep 16, 2008·The Journal of Nutritional Biochemistry·Debbie J MustacichMaret G Traber

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