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Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism*

Clinical Pharmacology & Therapeutics · 1996 · Vol. 59(5) · pp. 491–502

Kenneth E. Thummel(Vanderbilt University)Diarmuid O’Shea(University of Washington)Mary F. Paine(Vanderbilt University)Danny D. Shen(University of Washington)Kent L. Kunze(Vanderbilt University)James D. Perkins(Vanderbilt University)G. Wilkinson✉(University of Washington)

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Abstract

These results show that the small intestine can be a major site for presystemic, CYP3A-mediated metabolism after oral administration. Moreover, it appears that this represents a true first-pass effect. In addition, intestinal and hepatic metabolism may be important factors in interindividual variability in disposition after oral administration of midazolam and similar CYP3A substrates. Finally, intestinal localization of CYP3A may be significant in metabolism-based drug-drug interactions.

Pharmacogenetics and Drug Metabolism Drug Transport and Resistance Mechanisms Pharmacological Effects and Toxicity StudiesCYP3AFirst pass effectMidazolamBioavailabilityPharmacokineticsMicrosomeMetabolismDrug metabolismOral administrationMetabolite

MeSH terms

Administration, OralAdultBiological AvailabilityBlood ProteinsCytochrome P-450 Enzyme SystemEpitheliumFemaleHumansMixed Function OxygenasesInjections, IntravenousIntestine, SmallMaleMicrosomesMicrosomes, LiverMidazolam

Citations

617

FWCI

38.53

field-weighted impact

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100%

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Cited by

The Prediction of Human Pharmacokinetic Parameters from Preclinical and In Vitro Metabolism Data