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Effect of OATP1B1 ( SLCO1B1 ) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers
Author(s) -
Chung JaeYong,
Cho JooYoun,
Yu KyungSang,
Kim JungRyul,
Oh DalSeok,
Jung HyeRyung,
Lim KyoungSoo,
Moon KiHo,
Shin SangGoo,
Jang InJin
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.07.003
Subject(s) - pitavastatin , pharmacokinetics , cmax , pharmacology , area under the curve , chemistry , genotype , hyperlipidemia , medicine , endocrinology , biochemistry , atorvastatin , gene , diabetes mellitus
Background Pitavastatin is a potent, newly developed 3‐hydroxy‐3‐methylglutaryl–coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1B1 ( OATP1B1 ) alleles * 1a , * 1b , and * 15 on the pharmacokinetics of pitavastatin. Methods Twenty–four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1–8 mg) were further investigated. Subjects were grouped according to OATP1B1 genotype. Dose–normalized area under the plasma concentration–time curve (AUC) and peak plasma concentration (C max ) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. Results Dose‐normalized pitavastatin AUCs for * 1b/ * 1b (group 1), * 1a/ * 1a or * 1a/ * 1b (group 2), and * 1a/ * 15 or *1b/*15 (group 3) were 38.8 ± 13.3, 54.4 ± 12.4, and 68.1 ± 16.3 ng · h · mL −1 · mg −1 (mean ± SD), respectively, with significant differences between all 3 groups ( P = .008) and between subjects carrying and those not carrying the *15 allele ( P = .004). Dose‐normalized pitavastatin C max values were 13.2 ± 3.3, 18.2 ± 5.7, and 29.4 ± 9.6 ng · mL −1 · mg −1 in groups 1, 2, and 3, respectively, and also showed significant differences ( P = .003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose‐normalized AUC or C max values of pitavastatin lactone. Conclusion OATP1B1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the * 15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP1B1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone. Clinical Pharmacology & Therapeutics (2005) 78 , 342–350; doi: 10.1016/j.clpt.2005.07.003