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The pharmacokinetics of metoclopramide in normal rats and in rats with experimental renal and hepatic dysfunction

University of British Columbia

Metoelopramide (MCP), 4 amino-5-chloro-2-methoxy-N(2-diethyl -aminoethyl) benzamide, a procainamide derivative, is a potent antiemetic and gastric motility modifier. Clinically, MCP is used in gastrointestinal diagnostic examinations, treatment of various types of gastrointestinal disorders and as a pre- and post-operative anti-emetic. Very little pharmacokinetic information was available prior to this study. This thesis reports the pharmacokinetic study of MCP in normal rats and in rats with renal and hepatic dysfunction. The Pharmacokinetics of MCP in Normal Rats: The pharmacokinetics of MCP have been examined as a function of dose and route of administration. No significant first-pass metabolism was seen in urine and plasma studies (F = 0.9). The area under the plasma concentration vs. time curves (AUC) increased disproportionately while average plasma clearances (Cl[sub TB]) reduced with increasing dose indicating dose-dependent kinetics for MCP. However, the percentage of dose excreted as intact drug and de-ethylated metabolite (DE-MCP) was constant after administration of a range of intravenous doses (35 fold) indicating dose independent kinetics. The plasma and urine results could not be explained readily by conventional Michaelis-Menten kinetics. The elimination of MCP was proposed to be blood flow dependent . After a high dose, of MCP (35 mg/kg), the drug may transiently reduce perfusion to the eliminating organs (viz., liver, kidney, etc.). This hypothesis was supported by an initial reduction and then a subsequent return to control levels of the clearance of the blood flow indicator, indocyanine green, after MCP administration. Parallel to this observation, it was noted that the plasma half-life of MCP was initially prolonged (104 ± 14 minutes) and followed by a resumption of the normal elimination half-life (58 ± 7 minutes). A question remaining unresolved is why MCP does not undergo first-pass metabolism over the dose range studied. Kinetics of MCP in Hepatic Impaired Rats The hepatic impairment caused by carbon tetrachloride (CCI₄) increased the half-life and AUCs of MCP by approximately 3 fold [t[sub 1/2]: control = 52 ± 15min., test = 170 ±40 min.; AUC: control = 290 ± 50 mcg-min/ml, test = 840 ± 200 mcg-min/ml] while the Cl[sub TB] was diminished to a similar extent [control = 13 ± 1 ml/min; test = 4.6 ± 1.0 ml/min]. The volume of distribution (V[sub d]) did not change significantly. The renal clearance (Cl[sub R] of MCP was reduced slightly probably due to renal damage caused by CCI₄ [control =2.9 ml/min; test =2.3 ml/min]. The reduction of hepatic function caused a significant increase in the percentage of dose excreted as intact drug in urine [control = 20 ± 2%; test = 47 ± 7%]. However, the DE-MCP fraction was unaltered [control = 11 ± 3%; test = 9.3 ± 3%]. These results indicate that the liver is a major metabolic organ for MCP removal but extra- hepatic metabolism may also occur. Kinetics of MCP in Renal Impaired Rats The effect of renal dysfunction on the kinetics of MCP has been studied using two surgically [bilateral ureteral ligation (BUL) and two-step 5/6 nephrectomy (TSN)] and a chemically [uranyl nitrate (UN)] induced method providing a Wide range of renal impairment [creatinine clearance: control = 1.7-2.0 ml/ min; test = 0.03- 0.38 ml/min]. Renal damage was the highest in the UN group followed by the BUL and TSN groups. The t[sub 1/2] of MCP was significantly increased [control = 50-70 min, test = 130-160 min] and Cl[sub TB] [control = 11-16 ml/min, test = 3.4-7 ml/min] and Cl[sub R] [control = 2.0-2.9 ml/min, test = 0.2-0.7 ml/min] decreased while the V[sub d] [control = 4.0-4.5 L/kg, test = 3.2-4.4 L/kg] is only slightly decreased in all models studied. A positive correlation was observed between the Cl[sub TB], Cl[sub R] and nonrenal clearance with creatinine clearance (r² ≥ 0.97) indicating that the metabolic and renal clearances of MCP are related to renal function. The findings obtained from the hepatic and renal impairment models indicate that, besides the liver, the kidneys may also play an important role in metabolizing MCP. This may, in part, explain why MCP does not undergo first-pass metabolism in the rat.

Text

2010-03-31

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http://hdl.handle.net/2429/23191

Pharmaceutical Sciences

University of British Columbia

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