Eur J Clin Pharmacol (2011) 67:701–707DOI 10.1007/s00228-011-0994-7 Effects of SLCO1B1 polymorphisms on the pharmacokineticsand pharmacodynamics of repaglinide in healthy Chinesevolunteers Jiake He & Zhixia Qiu & Ning Li & Yang Yu & Yang Lu & Deen Han & Tingting Li &Di Zhao & Wei Sun & Fang Fang & Jianheng Zheng & Hongwei Fan & Xijing Chen Received: 12 August 2010 / Accepted: 7 January 2011 / Published online: 17 February 2011 tively (P=0.028, 0.032). The clearance in the former two Purpose Repaglinide is commonly used in the treatment of genotype groups was significantly attenuated (by 27.39 and patients with type 2 diabetes mellitus to reduce postprandial 28.55%, respectively) compared with individuals with hyperglycemia. The objective of this research was to study SLCO1B1*1B/*1B genotype (P=0.015, 0.019). No signif- the effects of SLCO1B1 polymorphisms on the pharmaco- icant differences in blood glucose-lowering effect were kinetics and pharmacodynamics of repaglinide in healthy observed among three genotype groups.
Conclusions SLCO1B1*1B/*1B genotype is associated Methods A total of 22 healthy young male participants were with reduced pharmacokinetic exposure after a single dose recruited from a pool of pharmacogenetically characterized oral administration of 2 mg repaglinide, including de- participants genotyped for SLCO1B1, CYP3A4, and CYP2C8 creased AUC0-∞ and increased clearance of repaglinide.
SNPs by polymerase chain reaction-restriction fragment Moreover, this polymorphism of SLCO1B1 has significant length polymorphism (PCR-RFLP). Volunteers with influence on the pharmacokinetics of repaglinide, but no CYP2C8*3 and CYP3A4*4 alleles were excluded from the clinical study. Then selected volunteers took part in theclinical pharmacokinetic study, receiving 2 mg repaglinide.
Keywords Repaglinide . SLCO1B1 polymorphisms .
Results Healthy participants with SLCO1B1*1A/*1B or *1A/*1A genotype and SLCO1B1 *15/*1A or *5/*1Agenotype had significantly higher AUC0-∞ than participants with SLCO1B1*1B/*1B genotype, with the former showing an increase over the latter of 39.81 and 42.09%, respec- J. He : Z. Qiu : N. Li : Y. Lu : D. Han : T. Li : D. Zhao : W. Sun : F. Fang J. Zheng X. Chen (*)Center for Drug Metabolism and Pharmacokinetics, Area under plasma concentration-time curve Nanjing, Jiangsu 210009, People's Republic of China Area under plasma concentration-time curve Bioanalysis Service, WuXi AppTec Co. Ltd, Shanghai 200131, People's Republic of China Clinical Pharmacology Laboratory, Nanjing First Hospital Area above blood glucose level-time curve Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210006, People's Republic of Chinae-mail: addition to the polymorphisms of SLCO1B1, theCYP2C8*3 variant allele could also be associated with Repaglinide is commonly used in the treatment of type 2 reduced plasma concentrations of repaglinide Fur- diabetes (T2D) to lower postprandial hyperglycemia As thermore, the Cmax and AUC0-∞ values of pitavastatin a short-acting insulin secretagogue, it reduces blood were about 71 and 85% higher in Chinese volunteers with glucose concentrations by enhancing glucose-stimulated the SLCO1B1 c.388GA and c.388GG genotypes than insulin release in pancreatic beta cells. Repaglinide is a those in volunteers with the SLCO1B1 c.388AA genotype drug of high plasma protein binding ratio (>98%) []. It is rapidly absorbed after oral administration with a bioavail- The available repaglinide pharmacogenetic studies ability about 60% During elimination, repaglinide is reported to date were almost exclusively performed in first taken up from the blood to hepatocytes by human Finnish populations. It still remains unknown whether the organic anion-transporting polypeptides 1B1 (OATP1B1) SLCO1B1 genotypes influence the pharmacokinetics and expressed on the basolateral membrane of hepatocytes and pharmacodynamics of repaglinide in the Chinese popula- then transformed into inactive metabolites via cytochrome tion. Due to the common interracial variability, we carried P-450 (CYP) 2C8 and 3A4 in liver [, The pharmaco- out a prospective and comprehensive pharmacogenetic and kinetics of repaglinide shows large interindividual variabil- pharmacodynamic study into repaglinide in healthy Chinese ity not only in healthy volunteers but also in T2D patients, mainly due to the genetic polymorphisms of drug trans-porter or metabolizing enzymes [].
Several single nucleotide polymorphisms (SNPs) have been identified in the SLCO1B1 gene encoding forOATP1B1. One common SNP of the SLCO1B1 gene, c.388A > G (p.Asn130Asp), has been associated withincreased OATP1B1 transport activity in vitro [, ], and All of the pharmacokinetic data were obtained from a the other common SNP c.521 T>C (p.Val174Ala) has been clinical pharmacokinetic study approved by the Human associated with reduced OATP1B1 transport activity in Ethics Committee of Nanjing First Hospital Affiliated to vitro and increased plasma concentrations of several of its Nanjing Medical University (Nanjing, China). Informed substrate drugs in the human body ]. Four haplotypes written consent was obtained from each of the subjects. A can be formed through these two SNPs, including total of 22 healthy young male participants were recruited SLCO1B1*1A (c.388A–c.521 T), *1B (c.388 G–c.521 T), from a pool of pharmacogenetically characterized partic- *5 (c.388A–c.521 C), and *15 (c.388 G–c.521 C) [].
ipants genotyped for SLCO1B1, CYP2C8, and CYP3A4 In East Asians, the frequencies of the c.388A>G and the SNPs. Volunteers with CYP2C8*3 and CYP3A4*4 alleles c.521 T>C variants are about 55–89% and 0–22% ], were excluded from the clinical study , ]. In all respectively. In Chinese, SLCO1B1*1B and *15 haplotype enrolled volunteers, four were genotyped with frequencies are 59.9 and 14%, respectively ].
SLCO1B1*1B/*1B (group 1), six with SLCO1B1 *1A/ Genetic polymorphism in SLCO1B1 is a major *1A, five with SLCO1B1 *1A/*1B, three with SLCO1B1 determinant of interindividual variability in the pharma- *15/*1A, and four with SLCO1B1 *5/*1A (Table cokinetics of repaglinide []. Subjects with the c.521CC Participants with SLCO1B1 *1A/*1B or *1A/*1A genotype genotype (including SLCO1B1*5 or SLCO1B1*15 homo- were combined into group 2, and participants with zygous haplotype) have 59 or 72% greater repaglinide SLCO1B1 *15/*1A or *5/*1A genotype were combined AUC0-∞ and higher mean plasma concentration compared into group 3. Each of the volunteers was healthy as with participants with c.521TC or c.521TT genotypes demonstrated by medical history, physical examination, At low administration dose of 0.5 mg repaglinide, the routine blood tests, and electrocardiography. All subjects SLCO1B1*1B/*1B haplotype has been associated with were nonsmokers, abstained from drugs for at least 2 weeks increased OATP1B1 transport activity and SLCO1B1*1A/ before entry into the study, and did not take any coffee or *1A with impaired activity in healthy Finnish []. In alcohol for 1 week before the study.
Genotyping of SLCO1B1, CYP2C8*3, CYP3A4*4 validated within the linear range of 0.1–50 ng/mL. The interday precision (expressed as the coefficient of variation)was 9.5% at 0.2 ng/mL, 9.5% at 2.0 ng/mL, and 1.7% at DNA was extracted from peripheral whole blood of each 20 ng/mL of repaglinide (n=5), while the intraday precision subject using a Tiangen DNA extraction kit (Biotech, was 10.8% at 0.2 ng/mL, 8.0% at 2.0 ng/mL, and 4.7% at Beijing, China). The genotypes of SLCO1B1 [c.521 T>C 20 ng/mL of repaglinide, respectively (n=15).
(rs4149056), c.388A> G (rs2306283)], CYP2C8*3, andCYP3A4*4 were identified by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) aspreviously described with little modification , ].
Pharmacokinetic parameters of repaglinide, such as Cmax PCR products were then digested with the respective and Tmax, were directly obtained from the measured data.
restriction enzymes (New England Biolabs, Beverly, MA, Other important pharmacokinetic parameters (T1/2, AUC0-8, USA or MBI Fermentas, Vilnius, Lithuania), and separated AUC0-∞, CL) were calculated using WinNonlin 5.0.1 with agarose gel of proper concentration (Basingstoke, (Pharsight, Mountain View, CA). Blood glucose decremen- Hampshire, England). Positive controls with definite spe- tal AAC0-3h, maximum glucose decrease, minimum glucose cific genotype templates and negative controls without concentration, and decremental extent were used to char- DNA templates were run with every assay to assess the acterize the blood glucose response to repaglinide.
Statistical analysis was performed using SPSS v. 12.0 Twenty-two healthy male Chinese volunteers (mean age (SPSS, Chicago, IL). Results were expressed as mean±SD 24.2±2.0 years, mean body mass index 21.9±1.3 kg/m2) in the text and tables and as mean±SEM in the figures for were entered into the trial. After an overnight fast, each clarity. Cmax and AUC data were logarithmically trans- of the volunteers ingested a single dose of 2 mg formed to fit a normal distribution. Analysis of variance repaglinide (NovoNorm, 1 mg tablet; NovoNordisk (one-way ANOVA) with Dunnett for post-hoc analysis was Bagsvaerd, Denmark) with 250 ml water at 07:30 AM used to compare the pharmacokinetic and pharmacodynam- and was not allowed to take in water until 2 h later.
ic parameters among different genotypes. Tmax data were Volunteers remained seated during the first 2 h and analyzed by the Kruskal-Wallis test. Pearson correlation received a standardized warm meal 3.5 h after repagli- coefficient was used to evaluate the relationship between nide administration. All the volunteers were directly the pharmacokinetic and pharmacodynamic parameters of under clinical supervision and avoided strenuous exer- repaglinide. A probability (P) of less than 0.05 was cises throughout the whole experiment. If obvious considered to be statistically significant.
symptoms of hypoglycemia occurred, 28 g glucosepowder dissolved in 200 ml water was given to thevolunteers. Timed blood samples (3 ml each) were drawn before and 0.167, 0.33, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0,4.0, 5.0, 6.0, 7.0, and 8.0 h after the administration of Pharmacokinetic parameters of repaglinide repaglinide. Plasma was then immediately separated andstored at −70°C for further analysis. Blood glucose After repaglinide administration, healthy participants in the concentrations were measured immediately after each SLCO1B1*1A/*1B or *1A/*1A genotype group (n=11) and blood sampling by the glucose oxidase method with the SLCO1B1 *15/*1A or *5/*1A genotype group (n=7) Glucose Assay Kit (Rongsheng Biotech, Shanghai, showed numerically but not significantly higher mean China). The interday coefficient of variation (CV) was plasma concentrations than the SLCO1B1*1B/*1B geno- 4.8% at 2.5 mmol/L, 3.6% at 12.5 mmol/L, and 4.5% at type group at most time points (P=0.348 and 0.389 at Cmax, respectively; P=0.008 and 0.022 at 5 h, respectively; P=0.018 and 0.010 at 6 h, respectively) (Fig. Table ). The Determination of plasma repaglinide concentrations AUC0-8 and AUC0-∞ in those two genotype groups werehigher by 39.8 and 39.8% (P=0.028 and 0.028, respective- Plasma concentrations of repaglinide were quantified by a ly), and 41.8 and 42.1% (P=0.033 and 0.032, respectively) liquid chromatographic-electrospray ionization-tandem (Fig. ), which was in good agreement with the character- mass spectrometry (LC-ESI-MS/MS) system [The istics of their transport activities. Moreover the CLs in limit of quantification was 0.1 ng/mL. The method was participants with the SLCO1B1*1A/*1B or *1A/*1A geno- decremental AAC0–3h (r=−0.035, P=0.883) in bloodglucose. After repaglinide administration, two volunteersgenotyped as SLCO1B1*5/*1A in the SLCO1B1 *15/*1Aor *5/*1A genotype group showed obvious symptoms ofhypoglycemia, and each received 28 g of glucose powder.
One volunteer genotyped as SLCO1B1*1A/*1B in theSLCO1B1*1A/*1B or *1A/*1A genotype group received28 g of glucose powder at 1 h and an additional 28 g at 2 hafter repaglinide intake. The blood glucose parameters ofthese three subjects were excluded from the final pharma-codynamic statistics analysis.
In this study, we investigated the influence of SLCO1B1 Fig. 1 Mean±SEM plasma concentration-time curve after a singleoral dose of 2 mg repaglinide in healthy participants with the genotypes on the pharmacokinetics and pharmacodynamics SLCO1B1*1B/*1B (n=4, open squares), SLCO1B1*1A/*1B or *1A/ of repaglinide in healthy Chinese. Healthy participants with *1A (n =11, open diamonds), and SLCO1B1*15/*1A or *5/*1A SLCO1B1*1B/*1B genotype had significantly smaller genotypes (n=7, open triangles). All the participants experienced an overnight fast and received a standardized warm meal 3.5 h after 0-∞ and larger CL than participants in the other two repaglinide administration. #P<0.05 vs. SLCO1B1*1B/*1B group genotype groups. The present findings on repaglinidepharmacokinetics were consistent with an enhanced hepaticuptake of repaglinide by OATP1B1 in the SLCO1B1*1B/ types and the SLCO1B1 *15/*1A or *5/*1A genotypes were *1B genotype , ]. Moreover, this paper first reported significantly lower (by 27.4 and 28.6%, respectively) than significant alterations in CL, but not in T1/2, after single those participants with the SLCO1B1*1B/*1B genotype (P= oral administration of 2 mg repaglinide. Such a phenome- non might be neglected in previous studies due to nostatistical differences in T1/2. The polymorphisms of OATP Pharmacodynamic parameters of repaglinide could have a profound influence on CL.
Pasanen et al. depicted the positions of c.388A > G (p.
The baseline blood glucose concentrations (P=0.770 and Asn130Asp) in the predicted second extracellular loop of 0.995, respectively), minimum concentrations (P=0.334 OATP1B1 and c.521 T > C (p.Val174Ala) in the predicted and 0.940, respectively), maximum decrease (P=0.854 and transmembrane domains []. The combined effect of amino 0.894, respectively), decremental AAC0–3h (P=0.944 and acid exchange and impaired protein sorting to the cell 0.955, respectively) as well as decremental extent (P=0.529 membrane will result in functional changes of OATP1B1, and 0.890, respectively) of lowering blood glucose showed making substrate specificity possible [–It is no significant differences among the three genotype reasonable to assume that the level of functional changes in groups after a single oral dose of 2 mg repaglinide, OATP1B1 may be intricate in individuals homozygous or while a tendency toward an effect of attenuated blood compound heteroygous for SLCO1B1 depending on repagli- glucose lowering presented in SLCO1B1*1B/*1B geno- nide dose, which may be a partial reason why the type (Table ). The AUC0-∞ in healthy participants with pharmacokinetic exposures in the SLCO1B1*1A/*1B or different genotypes did not significantly correlate with *1A/*1A genotype group and the SLCO1B1 *15/*1A or either the maximum decrease (r = 0.052, P= 0.828) or the *5/*1A genotype group were similar. However, it is also Table 2 Pharmacokinetic parameters of a single oral dose of 2 mg repaglinide for different SLCO1B1 genotypes Data are mean±SD# P<0.05 vs. SLCO1B1*1B/*1B group dose from 0.5 to 2 mg , there was no significant differencein blood glucose variables between different genotypes]. The following reasons could be possible explanations.
The adjustment of blood glucose is multifaceted andcomplicated. Blood glucose can be regulated by self-adjustment to a certain extent in healthy participants whena strong blood glucose-lowering effect is present at highconcentration, which could offset the blood glucose-lowering effect of repaglinide, resulting in no apparentassociation between pharmacodynamics and pharmacoki-netics. Repaglinide can stimulate insulin secretion frompancreatic ß-cells to reduce the blood glucose concentra-tion. However, the polymorphisms in insulin secretion andeffects sites, producing diversified ion channels andreceptors, would affect the direct efficiency of insulin]. Thus, it is suggested that even in healthy subjects, the Fig. 2 Individual AUC0-∞ values in healthy participants with threedifferent SLCO1B1 genotypes. For SLCO1B1*1B/*1B genotype same amount of insulin may be of different potencies, group, n=4; for SLCO1B1*1A/*1B or *1A/*1A genotype group, n=11; resulting in various blood glucose-lowering effects. The for SLCO1B1*15/*1A or *5/*1A genotype group, n=7. Some values detection of plasma insulin level after repaglinide adminis- were so close that they overlapped. #1: P=0.028 SLCO1B1*1A/*1B or tration could be a better indicator of the influence of *1A/*1A genotype vs. SLCO1B1*1B/*1B genotype. #2: P=0.032SLCO1B1 *15/*1A or *5/*1A genotype vs. SLCO1B1*1B/*1B genotype The frequencies of the c.388A> G and c.521 T>C variants are about 55–89% and 0–22%, respectively, in possible that some inevitable impact factors could affect the East Asians [, ]. And the widespread polymorphisms of pharmacokinetics of repaglinide, e.g., differences in gastric SLCO1B1 make them nonnegligible factors causing the interindividual and interracial variability in the clinical Pharmacodynamic findings were quite interesting. At a pharmacokinetics of repaglinide. In the Finnish population, dose of 2 mg, the AUC0-∞ of repaglinide did not genetic polymorphism in SLCO1B1 is a major determinant significantly correlate with either the maximum decrease of interindividual variability in the pharmacokinetics of or the decremental AAC0–3h in blood glucose level. It also repaglinide, and the effect of SLCO1B1 c.521 T > C seemed that participants with SLCO1B1*1B/*1B genotype polymorphism persists throughout the clinically relevant were not as sensitive to the blood glucose-lowering effect dose range [Thus, keeping a normal and comfort- as individuals in the other genotype groups (NS). Similarly, able pharmacokinetic exposure to repaglinide could be of in a study carried out by Kalliokoski et al. that escalated the Table 3 Blood glucose variables before and after a single oral dose of 2 mg repaglinide in healthy participants with different genotypes. Bloodglucose data were collected from 0 to 3 h after repaglinide administration because participants received a standardized warm meal at 3.5 h Data are mean±SD. After repaglinide administration, one volunteer genotyped as SLCO1B1*1A/*1B in SLCO1B1*1A/*1B or *1A/*1A genotypegroup and two volunteers genotyped as SLCO1B1*5/*1A in SLCO1B1 *15/*1A or *5/*1A genotype group showed obvious symptoms ofhypoglycemia, and each received 28 g of glucose powder. The blood glucose parameters of these subjects were excluded from the final statisticsanalysisa P=0.770 vs. SLCO1B1*1A/*1B or *1A/*1A genotype and P=0.995 vs. SLCO1B1 *15/*1A or *5/*1A genotypeb P=0.334 vs. SLCO1B1*1A/*1B or *1A/*1A genotype and P=0.940 vs. SLCO1B1 *15/*1A or *5/*1A genotype.
c P=0.854 vs. SLCO1B1*1A/*1B or *1A/*1A genotype and P=0.894 vs. SLCO1B1 *15/*1A or *5/*1A genotyped P=0.529 vs. SLCO1B1*1A/*1B or *1A/*1A genotype and P=0.890 vs. SLCO1B1 *15/*1A or *5/*1A genotypee P=0.944 vs. SLCO1B1*1A/*1B or *1A/*1A genotype and P=0.955 vs. SLCO1B1 *15/*1A or *5/*1A genotype During the clinical research, two volunteers genotyped as impaired membrane localization of the hepatocyte uptake trans-porter. J Biol Chem 277:43058–43063 SLCO1B1*5/*1A and one volunteer genotyped as 7. Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K SLCO1B1*1A/*1B showed obvious symptoms of hypogly- (2005) Functional characterization of SLCO1B1 (OATP-C) cemia. These side effects seem to be in accordance with high variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15 + pharmacokinetic exposure, but it is still necessary to C1007G, by using transient expression systems of HeLa andHEK293 cells. Pharmacogenet Genomics 15:513–522 investigate the genotype-adverse effect relationship and 8. Niemi M (2007) Role of OATP transporters in the disposition of elucidate molecular mechanisms. Beginning with an opti- mum dose and adjusting the dosage according to the 9. Kalliokoski A, Neuvonen PJ, Niemi M (2010) SLCO1B1 genotype if significant genotype-therapeutic effects are polymorphism and oral antidiabetic drugs. Basic Clin PharmacolToxicol 107:775–781 revealed and keeping proper maintenance dose will not only 10. Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms help develop a more secure and effective clinical use of in OATP-C: identification of multiple allelic variants associated repaglinide, reducing the risk of unwanted side effects such with altered transport activity among European- and African- as hypoglycemia, but also could relieve patients’ burden.
11. Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, Tsuji A, Due to ethical problems, we cannot conduct pharmacokinetic Yokoi T (2002) Genetic polymorphisms of human organic anion research in T2D patients at this time. But it remains to be transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele investigated whether the analogous response could appear in frequencies in the Japanese population and functional analysis. J Chinese T2D patients with the same genotype through more 12. Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, ingenious and secure experiments. Further investigations Kyrklund C, Backman JT, Kerb R, Schwab M, Neuvonen PJ, centering on the separate and combined effects of SLCO1B1 Eichelbaum M, Kivistö KT (2004) High plasma pravastatin polymorphisms on repaglinide disposition as well as a concentrations are associated with single nucleotide poly- potential risk evaluation during combination treatment in morphisms and haplotypes of organic anion transportingpolypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics T2D patients would be of great importance.
In conclusion, after a single oral administration of 2 mg 13. Kalliokoski A, Backman JT, Neuvonen PJ, Niemi M (2008) of repaglinide, SLCO1B1*1B/*1B genotype is associated Effects of the SLCO1B1*1B haplotype on the pharmacokinetics with reduced pharmacokinetic exposure such as decreased and pharmacodynamics of repaglinide and nateglinide. Pharma-cogenet Genomics 18:937–942 AUC0-∞ and enhanced clearance of repaglinide. Moreover, 14. Pasanen MK, Neuvonen PJ, Niemi M (2008) Global analysis of the polymorphism of SLCO1B1 has significant influence on genetic variation in SLCO1B1. Pharmacogenomics 9:19–33 the pharmacokinetics of repaglinide but no effects on its 15. Xu LY, He YJ, Zhang W, Deng S, Li Q, Zhang WX, Liu ZQ, Wang D, Huang YF, Zhou HH, Sun ZQ (2007) Organic aniontransporting polypeptide-1B1 haplotypes in Chinese patients. ActaPharmacol Sin 28:1693–1697 The study was supported by the 863 Hi-tech 16. Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Program of China (No. 2007AA02Z171).
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