title: Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote.
abstract: Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor used to lower blood low-density lipoprotein cholesterol, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight hundred healthy Chinese males were genotyped by polymerase chain reaction-pyrosequencing for ABCG2 34G>A, ABCG2 421C>A, SLCO1B1 521T>C, and CYP2C9*3 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C9*3 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was carried out using the WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G>A (0.275) and c.421C>A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared with subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin Cmax and area under the curve, AUC0-∞, were significantly higher, while the apparent oral clearance, CL/F, was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/421CA genotypes. Both t1/2 and Tmax were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G>A and c.421C>A variants was present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. These data suggest that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual.
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Zirui
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.) 207082@csu.edu.cn lqcai@yahoo.com.
authors.forename: Guo
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Tailin
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Biaobo
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Qi
authors.initials: Q
authors.lastname: Pei
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Guoping
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacology of Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China (Z.W., G.W., T.L., B.X., Y.P., H.S., Y.Z., Y.-S.Z.); Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (Q.P., G.Y.); Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha, Hunan, China (L.C.); and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China (Z.W.).
authors.forename: Yuan-Shan
authors.initials: YS
authors.lastname: Zhu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D005787:Gene Frequency / Q000187:drug effects / Q000235:genetics; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics; D011743:Pyrimidines / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005464:Fluorobenzenes; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9