Effects Of SLCO1B1 Polymorphism And Pitavastatin On The Pharmacokinetics Of Repaglinide In Chinese Healthy Volunteers

OBJECTIVE1. To investigate whether genetic polymorphisms in the organic anion transporting polypeptide 1B1 (OATP1B1) encoding gene SLCO1B1 affect the pharmacokinetics of repaginide in healthy Chinese subjects.2. To study the effect of pitavastatin on the pharmacokinetics of repaglinide and relationship with SLCO1B1 genetic polymorphism.METHODS1. Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of repaginideA single dose of 4 mg repaglinide was given orally in 16 healthy male volunteers. Plasma concentrations of repaglinide were determined by HPLC-MS-MS. SLCO1B1 c.388A>G (Asn130Asp) and c.521T>C (Val174Ala) polymorphisms were genotyped by PCR-RFLP and sequencing, respectively. SLCO1B1 haplotypes were inferred by using the software PHASE 2.0. The pharmacokinetic parameters were obtained by DAS Ver 2.0. The statistical analysis was performed with SPSS 13.0.2. Effect of pitavastatin on the pharmacokinetics of repaglinide in relationship with SLCO1B1 genetic polymorphismsForty male Chinese volunteers were genotyped in SLCO1B1. Twelve healthy volunteers with the SLCO1B1*1b/*1b genotype (n=4), SLCO1B1 *1a/*1a or *1a/*1b genotype (n=5), and SLCI1B1*1a/*15 or *1b/*15 genotype (n=3) were selected randomly. A randomized, placebo-controlled, crossover study with two phases and a washout period of 2 weeks was carried out. The two groups received 4 mg pitavastatin or placebo once daily for 5 days. On day 5,1 h after the last dose of pitavastatin or placebo administration,4 mg of repaglinide was orally administrated. Plasma concentrations of repaglinide and blood glucose concentrations after repaglinide administration were measured by HPLC-MS-MS and glucose oxidase method, respectively.The pharmacokinetic parameters were obtained by DAS Ver 2.0. The statistical analysis was performed with SPSS 13.0.RESULTS1. Effect of SLCOIBI genetic polymorphism on the pharmacokinetics of repaginideAUC0→t of repaginide in individuals with the SLCO1B1*1b/*1b, *1a/*1a+*1a/*1b,and*1a/*15+*1b/*15 genotypes were (62.88±20.00), (69.69±26.45), and (81.78±24.16)μg·L-1·h, respectively. Cmax of repaginide were (55.8±16.47), (52.04±16.96) and (58.5±34.28)μg·L-1 respectively. tmax of repaginide were (0.63±0.44), (0.82±0.35) and (0.58±0.14) h respectively. t1/2 of repaginide were (2.00±0.86), (2.40±2.43) and (1.53±0.43) h respectively. There was no significant difference in AUC0→8h and Cmax among the genotype groups.2. Effect of pitavastatin on the pharmacokinetics of repaglinide in relationship with SLCO1B1 genetic polymorphism1) Pitavastatin increased Cmax of repaglinide significantly (86.50±16.22μg·L-1 vs 99.42±22.44μg·L-1,P=0.003), but increased AUC0→t of repaglinide marginally (94.00±40.37μg·L-1·h vs 101.51±34.09μg·L-1·h,P=0.091). t1/2 of repaglinide showed a trend of increase though no significantly (1.65±0.32h vs 1.81±0.85h, P=0.456).2) No significant difference in repaglinide pharmacokinetics parameters were observed among SLCO1B1 genotype groups (both genotypes of individual polymorphism and haplotype combined genotypes) in either placebo or pitavastatin treatment period (P>0.05). Interaction between pitavastatin and SLCO1B1 genotype on pharmacokinetics of repaglinide was not obvious.3) No significant difference in the blood glucose-lowering response of repaglinide was observed between the pitavastatin and placebo treatment period.CONCLUSION1. SLCO1B1 genetic polymorphism had no effect on the pharmacokinetic profile of repaglinide. After repaglinide administration, higher concentrations were seen in the SLCO1B1*15 carriers.2. Pitavastatin can increase plasma concentrations of repaglinide independent of SLCO1B1 genetic polymorphism, but has no effect on pharmacodynamics of repaglinide in healthy volunteers.