Clofibric acid (CA), an anti-hyperlipidaemic agent, possesses a carboxylic acid functional group and is metabolised to an acyl glucuronide conjugate (CAG). Acyl glucuronides are intrinsically reactive metabolites of carboxylate drugs, and are capable of undergoing hydrolysis, intramolecular rearrangement, and covalent binding to macromolecules. / The purpose of this study was to determine the hepatic disposition of CA and CAG using the isolated perfused rat liver (IPRL). A pharmacokinetic model was devised to interpret the results. / Livers of male Sprague-Dawley rats were perfused under single-pass conditions with protein- and erythrocyte- free perfusate, containing CA, at a constant flow rate of 30mL/min. Outflow samples were collected into tubes containing ortho-phosphoric acid solution, which stabilised the samples, and analysed using HPLC method. / A study of the effect of CA concentration in perfusate medium on the hepatic disposition of the compound suggested that the pharmacokinetics of CA are linear from 0.2 to 1.0mg/L. Above this inflow concentration (at CA 5mg/L), the hepatic extraction ratio (E) and hepatic clearance (CL) decreased significantly (P < 0.05). Results of a drug interaction study indicated that probenecid (0.02mM) co administration significantly reduced (P < 0.05) the E and CL of CA, while paracetamol (0.02mM) did not change the pharmacokinetic parameters of CA. / The study improved our understanding of CA disposition in the liver and the potential impact of CA and probenecid coadministration. / Thesis (MApSc(Pharmacy))--University of South Australia, 2006.
| Identifer | oai:union.ndltd.org:ADTP/267321 |
| Creators | Wiedyaningsih, Chairun. |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | copyright under review |
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