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 language | English (US) |
|---|---|
| Pages (from-to) | 14-24 |
| Number of pages | 11 |
| Journal | Clinical Pharmacology and Therapeutics |
| Volume | 60 |
| Issue number | 1 |
| State | Published - Jul 1996 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pharmacology
Cite this
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 journal › Article
}
TY - JOUR
T1 - First-pass metabolism of midazolam by the human intestine
AU - Paine, Mary F.
AU - Shen, Danny D.
AU - Kunze, Kent L.
AU - Perkins, James D.
AU - Marsh, Christopher L.
AU - McVicar, John
AU - Barr, Darlene M.
AU - Gillies, Bruce S.
AU - Thummel, Kenneth E.
PY - 1996/7
Y1 - 1996/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0029738490&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029738490&partnerID=8YFLogxK
M3 - Article
C2 - 8689807
AN - SCOPUS:0029738490
VL - 60
SP - 14
EP - 24
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
IS - 1
ER -