{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T04:03:18Z","timestamp":1793419398203,"version":"4.5.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T00:00:00Z","timestamp":1331510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel.<\/jats:p><jats:p>\u2022\u2003The pharmacogenetics of <jats:italic>SLCO1B3<\/jats:italic> is not well characterized and previous <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> studies reported conflicting results with regards to the functional effects of the limited number of <jats:italic>SLCO1B3<\/jats:italic> polymorphisms that were studied.<\/jats:p><jats:p>\u2022\u2003Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of <jats:italic>SLCO1B3<\/jats:italic> pharmacogenetics might provide clinical benefits in guiding docetaxel dosing.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003The <jats:italic>SLCO1B3<\/jats:italic> gene was comprehensively screened in the local healthy Asian populations (<jats:italic>n<\/jats:italic>= 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype\u2010tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (<jats:italic>n<\/jats:italic>= 50).<\/jats:p><jats:p>\u2022\u2003Genotypic\u2010phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G&gt;A, 699G&gt;A(Met233Ile), IVS12\u20105676A&gt;G, and *347_*348insA] was the critical determinant of docetaxel disposition.<\/jats:p><jats:p>\u2022\u2003This study suggests that the comprehensive screening and haplotypic linkage analysis of <jats:italic>SLCO1B3<\/jats:italic> can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups.<\/jats:p><jats:p><jats:bold>AIMS<\/jats:bold> To completely screen the <jats:italic>SLCO1B3<\/jats:italic> gene in three distinct healthy Asian populations (Chinese, Malay and Indian, <jats:italic>n<\/jats:italic>= 168) and investigate the influence of haplotype\u2010tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold> Genomic DNA of individuals was screened for <jats:italic>SLCO1B3<\/jats:italic> polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold> A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15\u2010htSNPs were identified. The <jats:italic>SLCO1B3<\/jats:italic> haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (<jats:italic>P<\/jats:italic>= 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G&gt;A, 699G&gt;A(Met233Ile), IVS12\u20105676A&gt;G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration\u2212time curve (AUC(0,\u221e)): <jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>= 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,\u221e) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (<jats:italic>P<\/jats:italic>= 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (<jats:italic>P<\/jats:italic>= 0.002). The functional <jats:italic>SLCO1B3<\/jats:italic> haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR\u2010890 binding site in the 3\u2032\u2010untranslated region which may influence the transport characteristics of <jats:italic>SLCO1B3<\/jats:italic>.<\/jats:p><jats:p><jats:bold>CONCLUSIONS<\/jats:bold> This study highlights the importance of <jats:italic>SLCO1B3<\/jats:italic> polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2011.04123.x","type":"journal-article","created":{"date-parts":[[2011,10,13]],"date-time":"2011-10-13T14:32:50Z","timestamp":1318516370000},"page":"606-618","source":"Crossref","is-referenced-by-count":39,"title":["Influence of <i>SLCO1B3<\/i> haplotype\u2010tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients"],"prefix":"10.1111","volume":"73","author":[{"given":"Sin Chi","family":"Chew","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Sandanaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onkar","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eng Huat","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Teck","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmund J. 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