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 substrate using midazolam as a model compound.


METHODS
Midazolam was administered intravenously (1 mg) or orally (2 mg) to 20 healthy young subjects (10 men and 10 women) in a random fashion, and the disposition of 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 values of midazolam. Despite complete oral absorption, measured oral bioavailability 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 extraction ratio (0.43 +/- 0.24) that was similar to that of the liver (0.44 +/- 0.14). 1'-Hydroxymidazolam was extensively but variably formed in vitro by both hepatic and intestinal microsomes and, although the intrinsic clearance (V(max)/Km) was higher in the liver preparations (540 +/- 747 versus 135 +/- 92 microliters/min/mg protein), this difference was not statistically significant.


CONCLUSIONS
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.
Thummel
K E
KE
School of Pharmacy, University of Washington, Seattle, USA.
O'Shea
D
D
Paine
M F
MF
Shen
D D
DD
Kunze
K L
KL
Perkins
J D
JD
Wilkinson
G R
GR
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology*; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011485:Protein Binding; D012044:Regression Analysis; D012737:Sex Factors
D001798:Blood Proteins; D018757:GABA Modulators; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D008874:Midazolam