First-pass metabolism of midazolam by the human intestine

Mary F. Paine, Danny D. Shen, Kent L. Kunze, James D. Perkins, Christopher L. Marsh, John McVicar, Darlene M. Barr, Bruce S. Gillies, Kenneth E. Thummel

Research output: Contribution to journalArticle

407 Citations (Scopus)

Abstract

The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1'-hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients; After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1'-hydroxymidazolam, and l'-hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1'-hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration, For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 ± 0.18, For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 ± 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different(p = 0.009). Collectively, these results show that the small intestine contributes significantly to the first-pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first-pass metabolism may be a general phenomenon for all high-turnover CYP3A4 substrates.

Original languageEnglish (US)
Pages (from-to)14-24
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume60
Issue number1
StatePublished - Jul 1996
Externally publishedYes

Fingerprint

Midazolam
Intestines
Cytochrome P-450 CYP3A
Viscera
Blood Vessels
Liver
Glucuronides
Intestinal Mucosa
Small Intestine
Reperfusion
Liver Diseases
Tissue Donors

ASJC Scopus subject areas

  • Pharmacology

Cite this

Paine, M. F., Shen, D. D., Kunze, K. L., Perkins, J. D., Marsh, C. L., McVicar, J., ... Thummel, K. E. (1996). First-pass metabolism of midazolam by the human intestine. Clinical Pharmacology and Therapeutics, 60(1), 14-24.

First-pass metabolism of midazolam by the human intestine. / Paine, Mary F.; Shen, Danny D.; Kunze, Kent L.; Perkins, James D.; Marsh, Christopher L.; McVicar, John; Barr, Darlene M.; Gillies, Bruce S.; Thummel, Kenneth E.

In: Clinical Pharmacology and Therapeutics, Vol. 60, No. 1, 07.1996, p. 14-24.

Research output: Contribution to journalArticle

Paine, MF, Shen, DD, Kunze, KL, Perkins, JD, Marsh, CL, McVicar, J, Barr, DM, Gillies, BS & Thummel, KE 1996, 'First-pass metabolism of midazolam by the human intestine', Clinical Pharmacology and Therapeutics, vol. 60, no. 1, pp. 14-24.
Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, McVicar J et al. First-pass metabolism of midazolam by the human intestine. Clinical Pharmacology and Therapeutics. 1996 Jul;60(1):14-24.
Paine, Mary F. ; Shen, Danny D. ; Kunze, Kent L. ; Perkins, James D. ; Marsh, Christopher L. ; McVicar, John ; Barr, Darlene M. ; Gillies, Bruce S. ; Thummel, Kenneth E. / First-pass metabolism of midazolam by the human intestine. In: Clinical Pharmacology and Therapeutics. 1996 ; Vol. 60, No. 1. pp. 14-24.
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