Effect of polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the pharmacokinetics of lovastatin in healthy Chinese volunteers

Guilian Zhao; Mei Liu; Xiujun Wu; Guofei Li; Feng Qiu; Jingkai Gu; Limei Zhao

doi:10.2217/pgs.16.31

Effect of polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the pharmacokinetics of lovastatin in healthy Chinese volunteers

Pharmacogenomics. 2017 Jan;18(1):65-75. doi: 10.2217/pgs.16.31. Epub 2016 Dec 14.

Authors

Guilian Zhao^{1

2}, Mei Liu^{1

3}, Xiujun Wu⁴, Guofei Li¹, Feng Qiu¹, Jingkai Gu⁵, Limei Zhao¹

Affiliations

¹ Department of Pharmacy, Shengjing Hospital of China Medical University, No. 36 Sanhao Street Heping District, Shenyang 110004, China.
² Department of Pharmacology, Shenyang Pharmaceutical University, No. 103 Wenhua Road Shenhe District, Shenyang 110016, China.
³ Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road Shenhe District, Shenyang 110016, China.
⁴ Laboratory of Clinical Pharmacokinetics of TCM, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No. 33 Beiling Street Huanggu District, Shenyang 110032, China.
⁵ Research Center for Drug Metabolism, College of Life Science, Jilin University, No. 2699 Qianjin Street Chaoyang District, Changchun 130021, China.

PMID: 27967318
DOI: 10.2217/pgs.16.31

Abstract

Aim: This study examined whether gene polymorphisms (CYP3A4, ABCG2, SLCO1B1, NR1I2, PPARA and NFKB1) influenced the pharmacokinetics of lovastatin in Chinese healthy subjects.

Patients & method: Plasma concentrations of lovastatin and lovastatin acid were quantified using LC/MS/MS.

Results: PPARA c.208+3819 G allele carriers had approximately twofold higher AUC_0-∞ and C_max of lovastatin than wild-type (PPARA c.208+3819 AA) subjects. After adjustment for the PPARA variants, subjects with the SLCO1B1 521TT genotype had approximately 50% lower AUC_0-∞ of lovastatin acid than those with 521TC/CC genotypes, while the AUC_0-∞ of lovastatin lactone in NFKB1-94 DD wild-type carriers was twofold higher than in mutant homozygotes carriers.

Conclusion: Gene polymorphisms of PPARA, SLCO1B1 and NFKB1 affected the pharmacokinetics of lovastatin.

Keywords: ABCG2; CYP3A4; NFKB1; NR1I2; PPARA; SLCO1B1; lovastatin; lovastatin acid; pharmacokinetics.

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
Asian People / genetics*
Cytochrome P-450 CYP3A / genetics
Healthy Volunteers
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
Liver-Specific Organic Anion Transporter 1 / genetics
Lovastatin / blood
Lovastatin / pharmacokinetics*
NF-kappa B p50 Subunit / genetics
Neoplasm Proteins / genetics
PPAR alpha / genetics
Polymorphism, Single Nucleotide / genetics*
Pregnane X Receptor
Receptors, Steroid / genetics

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Liver-Specific Organic Anion Transporter 1
NF-kappa B p50 Subunit
NFKB1 protein, human
NR1I2 protein, human
Neoplasm Proteins
PPAR alpha
Pregnane X Receptor
Receptors, Steroid
SLCO1B1 protein, human
Lovastatin
Cytochrome P-450 CYP3A
CYP3A4 protein, human