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  • Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.

Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.

Pharmacogenetics and genomics (2015-09-15)
Hee Youn Choi, Kyun-Seop Bae, Sang-Heon Cho, Jong-Lyul Ghim, Sangmin Choe, Jin Ah Jung, Seok-Joon Jin, Hee-Sun Kim, Hyeong-Seok Lim
ABSTRACT

The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ammonium formate, ≥99.995% trace metals basis
Sigma-Aldrich
Diethyl ether, contains 1 ppm BHT as inhibitor, anhydrous, ≥99.7%
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Diethyl ether, ACS reagent, ≥98.0%, contains ≤2% ethanol and ≤10ppm BHT as inhibitor
Sigma-Aldrich
Diethyl ether, ACS reagent, anhydrous, ≥99.0%, contains BHT as inhibitor
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Diethyl ether, puriss., contains ~5 mg/L 2,6-di-tert.-butyl-4-methylphenol as stabilizer, meets analytical specification of Ph. Eur., BP, ≥99.5% (GC)
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Diethyl ether, contains BHT as inhibitor, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8% (GC)
Sigma-Aldrich
Diethyl ether, anhydrous, ACS reagent, ≥99.0%, contains BHT as inhibitor
Sigma-Aldrich
Ammonium formate, reagent grade, 97%
Sigma-Aldrich
Ammonium formate solution, BioUltra, 10 M in H2O
Sigma-Aldrich
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