Nonlinear bioavailability of metoclopramide in the rat: evidence for saturable first-pass metabolism.

Abstract

In vivo and in vitro experiments were conducted in rats to examine the possibility of either extrahepatic metabolism or saturable first-pass effect as an explanation for the unusual presystemic clearance of metoclopramide (I) previously reported. In vivo studies involved two-thirds hepatectomized rats and animals pretreated with carbon tetrachloride to induce hepatic necrosis, whereas in vitro studies involved incubation of equal amounts of I (5.0 mumol/mL) with various tissue homogenates (viz., liver, kidney, and lung) or their 9000 X g supernatant fractions. Results suggest that the metabolism of I principally occurs in the rat liver, and there was no evidence suggesting the involvement of kidney or lung tissue in the metabolism of I. Forty-eight-hour cumulative urinary excretion studies following oral and intravenous administration of less than or equal to 5.0 mg/kg of metoclopramide hydrochloride were conducted. The bioavailability (F) values of I at dosage levels 0.1, 0.5, 1.0, and 5.0 mg/kg were 0.49, 0.75, 0.77, and 0.83, respectively. It is concluded that the liver is the primary organ for the metabolism of I in the rat and that the drug exhibits dose-dependent hepatic first-pass metabolism.

• Authors: R P Kapil, J E Axelson, R Ongley, J D Price
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 73 Issue 2 Pg. 215-8 (Feb 1984) ISSN: 0022-3549 [Print] United States
• PMID: 6707886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Metoclopramide
• Diazepam

Topics

• Animals
• Biological Availability
• Carbon Tetrachloride Poisoning (metabolism)
• Diazepam (metabolism)
• Hepatectomy
• Kidney (metabolism)
• Kinetics
• Liver (metabolism)
• Lung (metabolism)
• Male
• Metoclopramide (metabolism)
• Rats
• Rats, Inbred Strains