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The organic anion transporting polypeptides (OATP/Oatp) are products of the solute carrier organic anion (<i>SLCO/Slco</i>) transporter gene superfamily and constitute a major class of polyspecific membrane solute carriers at the basolateral membrane of hepatocytes.  Alterations in Oatp hepatic drug uptake have the potential to alter the clinical pharmacokinetics, efficacy and safety of a given drug.  Similarly to their regulation of cytochrome P450 enzymes (CYP450) nuclear receptors (NR), such as the pregnane x receptor (PXR) and constitutive androstane receptor (CAR) have been implicated in the transcriptional regulation of Oatps. Dose response experiments were performed using known PXR and CAR activators in male Sprague Dawley rats to ascertain the effects of NR activation on hepatic Oatp expression.  Dexamethasone, pregnenolone-16α-carbonitrile (PCN), 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or Phenobarbital (PB) were administered for 72h and Taqman real time PCR used to quantify transcript levels and Western blots used to quantify transporter proteins.  Only Oatp1a4 displayed responsiveness to NR activation, Oatp1a1 and Oatp1b2 levels are not altered by NR regulation.  Oatp1a4 mRNA and protein levels were only increased by the PXR ligands, dexamethasone and PCN, dexamethasone being the more potent PXR activator compared to PCN.  Dexamethasone resulted in a statistically significant 8-fold induction of Oatp1a4 mRNA with a maximal increase in response occurring at 50mg/kg (12703 ± 1985 copies/ng RNA compared with control 1540 ± 193 copies/ng RNA, p &lt; 0.001). Increasing doss of 100 mg/kg and 150 mg/kg did not result in increased Oatp1a4 levels.  Western blotting showed that dexamethasone and PCN resulted in an increase of Oatp1a4 protein.  The CAR activator, PB, increased Oatp1a4 protein levels; however this is likely to be via a post transcriptional mechanism as there was no concurrent increase in Oatp1a4 mRNA.

This thesis describes investigations of reactions of hydrazones and their N-anions via the imino carbon atom; these reactions show umpolung reactivity. The conversion of the derived azo products into synthetically useful compounds (e.g. 4-ketoesters, 4-ketoacids, 4-ketonitriles, alkanes, amines) is also described. Reactions of ṯ-butylhydrazone anions with enoic esters are described. 4-ṯ-Butylazoesters were formed on reaction with methyl crotonate. The 4-ṯ-butylazoesters derived from aldehyde ṯ-butylhydrazones were converted by tautomerisation of the azo function and hydrolysis of the resultant ṯ-butylhydrazone to 4-ketoesters or 4-ketoacids in 47-60% yield. Other Michael type electrophiles investigated gave negligible yields of C-adducts. ṯ-Butylhydrazones of aliphatic aldehydes were found to give ene adducts with methyl acrylate or aerylonitrile on reflux in xylene for 24h. The resultant azo compounds were converted into 4-ketoesters (75-90%) or 4-Ketonitriles (18- 75%) by tautomerisation and hydrolysis. Other potential enophiles investigated did not give C-adducts. A synthesis of a ṯ-butylazoalkene from an aldehyde ṯ- butylhydrazone and benzaldehyde by addition and dehydrative elimination is described. The reduction of ṯ-butylazoalkenes with zinc-acetic acid is described. The C-alkylation of tritylhydrazone anions with alkyl halides gave tritylazoalkanes. Tritylazoalkanes decomposed by homolytic fragmentation with dinitrogen evolution above -20°C. Trapping with ethanethiol of the resultant radicals gave alkanes in 27-69% yield. The last section describes investigations of the anions of various secondary alkyl hydrazones for C-reaction, and attempted reduction of the resultant azoalkanes to amines Isopropyl- and cyclohexylhydrazones gave low yields of Cadducts. 2,4-Dimethylpent-3-yl- (DMP) and 3,3-dimethylbut- 2-ylhydrazones (TBM) gave good yields of C-adducts. Direct reduction of the azoalkanes to amines was not achieved Azoalkanes derived by alkylation of ketone DMP or TBM hydrazones were tautomerised and hydrolysed to hydrazines in low yield. Reduction of a so-formed hydrazine gave an amine, but in low overall yield (14%).

Reprints of 2 articles published by the author bound in back of publication / iv, 170 leaves : ill. ; 26 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Organic Chemistry, 1976

Thesis (M.S. - Hydrology and Water Resources)--University of Arizona, 1984. / Bibliography: leaves 61-63.