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Title:Pharmacokinetics and renal clearance of morphine and its two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide in the rabbit
Author(s):Davis, Carol Ann
Doctoral Committee Chair(s):Koritz, Gary D.
Department / Program:Veterinary Biosciences
Discipline:Veterinary Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Health Sciences, Pharmacology
Abstract:The pharmacokinetics of morphine and renal clearance of morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G) and morphine (M) were studied following intravenous (IV) administration of single doses of morphine (1.5 mg/kg) alone, in the presence of cimetidine as a loading dose (10 mg/kg) and repeat doses (5 mg/kg) every thirty minutes or in the presence of probenecid as a loading dose (10 mg/kg) and repeat doses (5 mg/kg) every thirty minutes. Plasma concentration of M versus time data generated in the present study were analyzed using a bi-exponential equation. The effect of cimetidine and probenecid on the pharmacokinetics of M and renal clearance of M, M3G, and M6G were investigated.
After IV administration of morphine a rapid distribution phase (0.1313 $\pm$ 0.038) was followed by a slower elimination phase (0.0122 $\pm$ 0.001). The half-life was 53 minutes, Vd$\rm\sb{ss}$ was 6.2 L/kg and C1$\rm\sb{s}$ was 90 ml/min/kg. The Vd$\rm\sb{ss}$ of morphine was reduced in the presence of cimetidine (5.7 L/kg) and in the presence of probenecid (4.8 L/kg). The C1$\rm\sb{s}$ was unchanged in the presence of cimetidine (88 ml/min/kg) or probenecid (78 ml/min/kg).
Morphine, M3G and M6G were excreted by the kidney with approximately 27% of the dose recovered in the urine at six hours (M 11%, M3G 15%, M6G, 1%). In the presence of cimetidine, 30% of the dose was recovered (M 6%, M3G 23%, M6G 1%) and in the presence of probenecid, 52W of the dose was excreted (M 19%, M3G 32% and M6G 1%). The redistribution of morphine, by cimetidine, increased the metabolism of morphine and subsequent excretion of more M3G in the urine. With probenecid, redistribution not only enhanced metabolism and excretion of more M3G, but also increased the amount of M excreted.
Renal clearance of M was 12.1 ml/min/kg (filtration and secretion), of M6G was 5.5 ml/min/kg (filtration and secretion), and of M3G was 1.6 ml/min/kg (filtration). Cimetidine, an inhibitor of organic cation renal tubular secretion, partially blocked the secretion of M (7.9 ml/min/kg). Probenecid, an inhibitor of anion renal tubular secretion, blocked the secretion of M6G (3.2 ml/min/kg).
Issue Date:1996
Rights Information:Copyright 1996 Davis, Carol Ann
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9702497
OCLC Identifier:(UMI)AAI9702497

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