ORAL FIRST-PASS ELIMINATION OF MIDAZOLAM INVOLVES BOTH GASTROINTESTINAL AND HEPATIC CYP3A-MEDIATED METABOLISM

Objective: To determine in humans the relative roles of intestinal and hepatic metabolism in the oral first-pass elimination of a CYP3A subs trate using midazolam as a model compound. Methods: Midazolam was admi nistered intravenously (1 mg) or orally (2 mg) to 20 healthy young sub jects (10 men and 10 women) in a random fashion, and the disposition o f the drug and its 1'-hydroxy metabolite were determined, In separate in vitro studies, the CYP3A-mediated formation of 1'-hydroxymidazolam by human hepatic and intestinal microsomes was investigated. Results: No gender-related differences were noted in either the systemic (370 /- 114 ml/min [mean +/- SD]) or oral (1413 +/- 807 ml/min) clearance v alues of midazolam. Despite complete oral absorption, measured oral bi oavailability was on average about 50% less than that predicted on the assumption that only the liver contributed to first-pass metabolism. Pharmacokinetic estimation of the intestinal component indicated an ex traction ratio (0.43 +/- 0.24) that was similar to that of the liver ( 0.44 +/- 0.14). 1'-Hydroxymidazolam was extensively but variably forme d in vitro by both hepatic and intestinal microsomes and, although the intrinsic clearance (V-max/K-m) was higher in the liver preparations (540 +/- 747 versus 135 +/- 92 mu l/min/mg protein), this difference w as not statistically significant. Conclusions: These results show that the small intestine can be a major site for presystemic, CYP3A-mediat ed metabolism after oral administration, Moreover, it appears that thi s represents a true first-pass effect. In addition, intestinal and hep atic metabolism may be important factors in interindividual variabilit y in disposition after oral administration of midazolam and similar CY P3A substrates. Finally, intestinal localization of CYP3A may be signi ficant in metabolism-based drug-drug interactions.