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.

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Pharmaceuticals in the aquatic environment is an emerging issue and the risks they pose are mostly unknown. They are used in large amounts throughout the world and can enter the environment, as the active metabolite or unmetabolised, through excretion by people and improper disposal. As these drugs are designed to have specific biological effects in a specific organism (as well as sometimes having other non-specific side effects), their potential to cause effects within the environment is great. Clofibric acid (the major metabolite of the lipid lowering drug, Clofibrate) is non-biodegradable, highly motile, very persistent and frequently detected at μg/I levels in the environment. I studied possible effects of clofibric acid in fish, using different experimental approaches and endpoints. The studies involve two different species, and for one of these species, fish at different stages of development. The chapters within this thesis have presented the first evidence (albeit preliminary) of clofibric acid having effects on both adult and embryo fish. When fathead minnow embryos were exposed to clofibric acid, the effects seen included changes in the eggshell, time to hatch, hatchability, mortality and viability. Adult fathead minnow were similarly exposed and significant effects on specific parameters were also observed. These included effects on lipid metabolism, steroidogenesis and spermatogenesis - thought to be via cholesterol transport - as well as significant effects on the expression of several genes involved in lipid metabolism and detoxification. Exposure of juvenile (sexually undifferentiated) bream also found significant differences in some endpoints. Other results suggested, less pronounced effects of clofibric acid on some other parameters. The results from this research show that there are effects of clofibric acid in pathways which were not only unexpected in fish (for example, steroidogenesis, spermatogenesis and gene expression), but also at concentrations below those previously shown to have any biological effects on fish. These effects indicate that clofibric acid may potentially have an impact on fish fecundity, and even more worryingly, on human health for those people prescribed it.

Duplicated genes are present in the teleost fish lineage owing to a whole-genome duplication (WGD) event that occured ~ 230-400 million years ago. In the duplication-degeneration-complementation (DDC) model, partitioning of ancestral functions (subfunctionalization) and acquisition of novel functions (neofunctionalization) have been proposed as principal processes for the retention of duplicated genes in the genome. The DDC model was tested by analyzing the differential tissue-specific distribution of transcripts for the duplicated fatty acid-binding protein 10 (fabp10) genes in embryos, larvae and adult zebrafish (Danio rerio). The distribution of zebrafish fabp10a and fabp10b transcripts show a strikingly different tissue-specific pattern leading us to suggest that the zebrafish fabp10 duplicates had been retained in the genome owing to neofunctionalization. In another experiment to test the DDC model, transcriptional regulation of duplicated fabp genes was analyzed in zebrafish fed clofibrate, a peroxisome proliferator-activated receptor (PPAR) agonist. Clofibrate increased the steady-state level of both the duplicated copies of fabp1a/fabp1b.1, and fabp7a/fabp7b mRNA and heteronuclear RNA (hnRNA), but in different tissues of zebrafish. The steady-state level of fabp10a and fabp11a mRNA and hnRNA was elevated in liver of zebrafish, but not for fabp10b and fabp11b. We also investigated the effect of dietary fatty acids (FAs) and clofibrate on the transcriptional regulation of single copy fabp genes, fabp2, fabp3 and fabp6 in zebrafish. The steady-state level of fabp2 transcripts increased in intestine, while fabp3 mRNA increased in liver of zebrafish fed diets differing in FA content. In zebrafish fed clofibrate, fabp3 mRNA in intestine, and fabp6 mRNA in intestine and heart, was elevated. Whether the regulation of fabp gene transcription by clofibrate is controlled either directly or indirectly, the regulatory elements in the zebrafish fabp genes have diverged markedly since the WGD event, thereby supporting the DDC model.