有機陰離子運輸多胜肽(OATPs: Organic anion-transporting polypeptides)已被了解分布在許多組織中，其運輸機制不需要鈉離子輔助，可媒介很多內生性物質及藥物運送，對於物質的吸收及在組織分布與排除具有重要的調節功能。OATP1B3 為有機陰離子運輸多胜肽(OATPs)中的一個成員，特定存在於肝細胞基底膜，可運輸膽酸、甲狀腺賀爾蒙、類固醇共軛物及digoxin 等受質。
過去大多數的藥物交互作用原因，發生在肝臟代謝酵素間被誘導或抑制，而近年來也發現，藥物運輸器可能也是造成藥物交互作用原因之一：當藥物進出細胞競爭同一運輸器的運送，即會造成不良反應的發生。文獻有關OATP1B3 受質或抑制劑的資料有限，於是我們實驗想要探討在臨床用藥中哪些為OATP1B3 之高親和性物質。另一方面，基因多型性為藥物投予後個體反應差異的主因，過去研究中也發現OATP1B3 有兩個高頻率的單點核苷酸多型性(SNPs)-T334G (Ser112Ala) 和G699A(Met233Ile)，可能影響其對受質的特異性。我們有興趣了解其發生於台灣族群的分布頻率，以及探討這兩個SNPs 是否會影響OATP1B3 功能性，造成藥物在細胞與人體內的運輸力改變。
實驗首先以inhibition 試驗篩選46 種臨床常見用藥，其中發現paclitaxel 對OATP1B3 有最高的親合力(IC50= 0.098μM)。此外分析台灣族群300 個血液樣品，發現OATP1B3-T334G (Ser112Ala) 和G699A(Met233Ile)變異分別有72.5%和72%，並且兩者發生有很高的關聯性。於是我們欲探討這兩個SNPs 分別及同時存在的情況下是否影響OATP1B3此蛋白的表現量及運輸力。體外實驗發現，表現各種變異型OATP1B3 的HEK293 細胞在蛋白的表現量及運輸E217βG 能力並無顯著改變。人體試驗，我們使用telmisartan 這個由OATP1B3 專一性運送的受質，評估兩組同型合子野生型Ser112/Met233 和變異型Ala112/Ile233 的受試者對於telmisartan 在體內藥物動態的不同； 同時也必須考慮肝臟中代謝telmisartan 的酵素：UGT1A1 基因多型性之影響。在固定兩點常發生於健康受試者的UGT1A1 基因變異：UGT1A1*28 (A(TA)7TAA)和UGT1A1*6(G71R)的情況下，比較野生型和變異型受試者的telmisartan 在體內血中濃度變化，結果發現telmisartan 藥動參數在兩組並無明顯差異。以上結果顯示T334G (Ser112Ala) 和G699A (Met233Ile)變異，對於OATP1B3此蛋白運輸能力造成的影響較小，在體外和體內實驗中，分別運送E217βG和telmisartan 皆無明顯差別，但對於其他受質的重要性需要進一步研究。

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.

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