Hepatic first-pass metabolism of metoclopramide in the rat

Metoclopramide (MCP), a procainamide analog, is a potent antiemetic and gastric motility modifier. Clinically, it is used in gastro-intestinal (GI) diagnostic examinations, treatment of various types of GI disorders and as a pre-and postoperative antiemetic-antinausea antinauseant agent. It has been found recently that, after a low i.v. dose of MCP (≤15 mg.kg⁻¹) in rats, the nonrenal clearance approaches hepatic blood flow suggesting that the disposition of the drug may be perfusion limited. This further suggested that, following an oral dose, an appreciable extent of hepatic first-pass metabolism of MCP should occur. However, it was observed by the previous workers that there was insignificant hepatic first-pass metabolism of MCP following oral dosing ≥1 mg.kg⁻¹. Hypotheses of temporary saturation of the binding sites and metabolic pathways during the first passage through the liver as well as extrahepatic metabolism have been used to attempt to rationalize this observation. A four fold increase in the terminal half-life of MCP and a similar reduction in the total body clearance of MCP in rats as well as patients with renal impairment has been observed by previous investigators. These observations were unexpected since only about 20-25% of the MCP dose is excreted as intact drug in both the species suggesting that the renal elimination pathway is relatively unimportant. Hypotheses of reduced hepatic function secondary to renal injury or the loss of extrahepatic metabolic capabiltties due to kidney malfunction were made to explain the observed discrepancies. Prior to animal experimentation, an existing gas-liquid chromatographic-electron capture detector assay technique for the simultaneous analysis of MCP and it's mono-de-ethylated metabolite (De-MCP) was improved. The method was based on the acylation of these compounds with heptafluorobutyryl anhydride at 55°C for 60 minutes in the presence of 0.1 ml of 0.1M triethyl amine catalyst. A 1.8m x 2 mm (i.d.) glass column packed with 3% Silar-9CP on Chromosorb- W (H.P.)([sup R]) 100-120 mesh size was used. Complete baseline resolution between MCP and De-MCP was obtained. This thesis examines the lack of presystemic clearance (hepatic first-pass metabolism) and evidence of extra-hepatic metabolism of MCP, utilizing in-vivo and in-vitro studies. The in-vivo experiments included two-third (2/3rd) hepatectomy and carbon tetrachloride (CCl₄) pretreatment studies. An equal dose of MCP was administered intraperitoneally in test (2/3rd hepatectomised and CC1₄ pretreated) as well as control (sham operated and normal saline pretreated respectively) rats, and 48 hour cumulative urinary excretion studies of intact MCP and De-MCP were made. In both studies, the total amount of intact MCP recovered from the 48 hour cumulative urine of test rats was significantly higher than that of control rats, This suggested that the rat liver Is involved in the metabolism of MCP. In-vitro studies involved incubation of equal amounts of MCP (5 micromole.ml⁻¹) with various tissue homogenates (viz., liver, kidney and lung) and their 9000g supernatant fractions. Our studies suggest that the metabolism of MCP occurs in the rat liver and that De-MCP is further metabolised in the liver. Also, there was no evidence suggesting the involvement of kidney or lung tissues in the metabolism of MCP. Forty-eight hour cumulative urinary excretion studies, following oral and intravenous administration of 0.1, 0.5, 1.0 and 5.0 mg.kg⁻¹ of MCP were conducted. The bioavailability (F) of MCP was found to be non-linear, i.e. the 'F' value increased with increasing doses. This observation suggested that MCP undergoes dose-dependent hepatic first pass metabolism in the rat. An attempt to predict the bioavailability of MCP, on the basis of a non-linear model was also made. The experimental values of MCP bioavailability, at different doses, were found to be in agreement with the predicted values, suggesting that the bioavailability of MCP is non-linear and dose dependent.Pharmaceutical Sciences, Faculty ofGraduat