Nonlinear bioavailability of metoclopramide in the rat: evidence for saturable first-pass metabolism.
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.
D000818:Animals; D001682:Biological Availability; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D006498:Hepatectomy; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008787:Metoclopramide / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D008787:Metoclopramide; D003975:Diazepam