The Distribution Of SLCO1B1 In Chinese Hyperlipemia Patient And The Impact Of Its PolymorpHism On Efficacy Of Pitavastatin

BACKGROUNDS: Organic anion transporting polypeptide 1B1(OATP1B1) is a sodium independent bile acid transporter, also known asliver-specific transporter 1 (LST-1) or OATP-C, encoded gene SLCO1B1. It isspecifically expressed at the basolateral membrane of human hepatocytes andresponsible for the hepatocellular uptake of a variety of endogenous andforeign chemicals. Multiple single-nucleotide polymorpHisms (SNPs) havebeen identified in the human SLCO1B1 gene and some of them have beenfound to be associated with the disfunction of transport activity in vitro or invivo. Tirona et al. performed experiments with human OATP1B1-transfectedHeLa cells and found that T217C (OATPC*2), T521C (OATP-C*5), T1058C(OATP-C*6), G1463C (OATP-C*9), and A1964G (SLCO1B1*10) variantswere associated with significantly reduced transport activities in comparisonwith activities of the wild type, the transport activities ranged from 7% to53% of the value for the reference allele. PHarmacokinetics studies carriedout by Sugiyama et al. indicated 521T＞C mutant was associated withdecreased non-renal elimination of pravastatin and increased system exposureof this drug. The gene mutation frequency of 521T＞C in Japanese was about15.8%. Similarly, studies carried out by Zhang Wei et al. indicated that theallele frequency of 521T＞C in Chinese was about 14%,which means similarfrequency of this mutation may be happened in oriental population. This studyalso indicated that genetic polymorpHism in SLCO1B1 was a majordeterminant of interindividual variability in the serum bilirubin level.Moreover, subjects with 521C allele showed an attenuatedtotal-cholesterol-lowering effect compared with those homozygous for the521T allele.Pitavastatin is a selective and competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is widely called'super-tatin' as a consequence of its strong effect, compared with its smalldosage. In July 2003 it was authorized to go on sale in Japan for the first timeand today it is under the clinical trail pHaseⅢand is supposed to go on themarket in 2008 in China. PHarmacokinetics studies carried out by Jae-YongChung et al. indicated human OATP1B1 genetic polymorpHism significantlyimpacted the pHarmacokinetics of pitavastatin, its AUC and Cmax in subjectswho carried heterozygote OATP1B1*15 alleles was 1.4 and 1.8 times higherthan those who did not carry the same. Meanwhile, they predicted AUC andCmax of OATP1B1*15/*15 genetype was 2 or 3 times higher than that ofOATP1B1*1b/*1b, but whether OATP1B1 genetypes were involved inefficacy of pitavastin or not, depended on further clinical trials, aspHarmacokinetics of pitavastin among OATP1B1 genotypic groups were ofno statistic significance.OBJECTIVE: To determine the distribution characteristic of commonlyoccurred genetic polymorpHisms of OATP1B1 in Chinese essentialhyperlipidemia population. To discuss the impact of SLCO1B1 521T＞C and388G＞A genetic polymorpHism on the lipid-lowering effects of pitavastatinvia clinical trials.METHODS: 140 Chinese essential hyperlipidemia patients werescreened for SLCO1B1 alleles in our study. Polymerase chainreaction-restriction fragment length polymorpHism (PCR-RFLP) was used toidentify 388G＞A polymorpHism and a one-step tetra-primers method(ARMS-PCR) was developed for determination of 521T＞C mutation.Essential hyperlipidemia patients, whose genotypes were determined byARMS-PCR method, were selected by clinical test program.They weretreated with 2mg daily for 56 days. Serum total cholesterol (TC, considered asthe main therapeutic index), triglyeride (TG), high-density lipoproteins(HDL)and low-density lipoprotein (LDL) levels were determinedusing an automated analyzer. These indexes were used to analyze thedifferences of efficacy among various genetypes using repeatedmeasurements analysis of variance (ANOVA).The level of statisticalsignificance was set at P＜0.05. Meanwhile, vital sign, blood and urineroutine method,hepatic and renal functions were involved in safetyevaluation.RESULTS: The frequencies of the 388G＞A and 521T＞C variant allelesin Chinese essential hyperlipidemia population were 71.1% and 11.1%,respectively. The frequencies of 388G＞A mutant heterozygotes andhomozygotes were 40.7%and 50.7%, respectively, while 388A wild typehomozygotes being 8.6%. And the frequencies of 521T＞C mutantheterozygotes and homozygotes were 19.3% and 1.4%, respectively, while521T wild type homozygotes being 73.8%. 85 subjects finished the clinicaltrial according to the project.Triglyeride, high-density lipoprotein,low-density lipoprotein decreased significantly after the treatment, theefficiency of pitavastatin being up to 83.5%. We found no significantdifferences of the efficacy pitavastatin between subjects carrying theSLCO1B1 521T＞C and SLCO1B1388G＞A genotype (P＞0.05)。CONCLUSIONS: The frequencies of SLCO1B1 388G＞A and 521T＞Cvariants are relatively common to Chinese essential hyperlipidemiapopulation, which are similar to Chinese or Japanese healthy population, butsignificantly different from Caucasians and Blacks. SLCO1B1 521T＞C and388G＞A gene mutations may not be associate with the blood lipid-loweringefficacy of pitavastatin.