Nonlinear Bioavailability of Metoclopramide in the Rat: Evidence for Saturable First-Pass Metabolism

Autor: R. C. Ongley, John D. E. Price, R.P. Kapil, James E. Axelson
Rok vydání: 1984
Předmět:
Zdroj: Journal of Pharmaceutical Sciences. 73:215-218
ISSN: 0022-3549
DOI: 10.1002/jps.2600730218
Popis: 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.
Databáze: OpenAIRE
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