碩士 / 國立成功大學 / 藥理學研究所 / 95 / The organic anion transporting polypeptides (OATPs) form a superfamily of sodium-independent transport systems that mediate the transmembrane transport of a wide range of amphipathic endogenous and exogenous organic compounds. It is suggested that they may play a critical role in drug disposition. OATP1B3 is a liver-specific transporter, and expressed predominantly at the basolateral membrane of hepatocytes. Endogenous substrates for OATP1B3 include bile acids, thyroid hormones, steroid conjugates, and drugs such as digoxin.
Most drug-drug interaction involve inhibition of drug-metabolizing enzyme, and transporters are increasingly recognized as the likely mechanism. While little information is known about the possible factor of OATP1B3 in these interaction, its substrates or inhibitors are required to determined. On the other hand, it has been reported that genetic polymorphisms of T334G and G699A were frequently observed in the OATP1B3, and they might affect the substrate specificity. The aim of our study is to search selective inhibitors against OATP1B3 in clinical drugs and to assess the allele frequency of the polymorphism in Taiwanese population and functional analysis in vitro and in vivo.
In this study, we tested 46 clinical drugs inhibition effects in OATP1B3 expressed HEK293 cells, and found that paclitaxel was the most potent inhibitor (IC50= 0.098μM). In addition , the polymorphisms T334G (Ser112Ala) and G699A (Met233Ile) had a genotypic frequency with 72.5% and 72%, respectively (n=300). The two SNPs were also found with strong linkage. We attempt to know whether the SNPs have effect on protein expression and uptake activity. In vitro, we found that the protein level and the transport activity of E217βG in OATP1B3 SNP variants expressed in HEK293 cells were no different. We also examine the influence of OATP1B3 genetic variations on the pharmacokinetic of telmisartan in human to determine the expression levels in the two groups with haplotypes of homozygous Ser112/Met233 and Ala112/Ile233. Telmisartan has been suggested that predominantly transported by OATP1B3, and metabolized by UGT1A1 in the liver. Two major mutant of UGT1A1, UGT*28 (A(TA)7TAA), and UGT1A1*6(G71R) were fixed in the same genotype in two OATP1B3 haplotypes. Finally, no significantly difference was seen in the pharmacokinetics of telmisartan in different OATP1B3 genotype. These results suggest that these SNPs in SLCO1B3 appear to play a limited role in the OATP1B3 transport E217βG or telmisartan, and the clinical significance in other substrates remains to be investigated.
| Identifer | oai:union.ndltd.org:TW/095NCKU5550019 |
| Date | January 2007 |
| Creators | Chwen-ying Chen, 陳純瑩 |
| Contributors | Jin-ding Huang, 黃金鼎 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 72 |
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