Provider: Ingenta Connect Database: Ingenta Connect Content: application/x-research-info-systems TY - ABST AU - Choi, Hee Youn AU - Bae, Kyun-Seop AU - Cho, Sang-Heon AU - Ghim, Jong-Lyul AU - Choe, Sangmin AU - Jung, Jin Ah AU - Jin, Seok-Joon AU - Kim, Hee-Sun AU - Lim, Hyeong-Seok TI - Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid JO - Pharmacogenetics and Genomics PY - 2015-12-01T00:00:00/// VL - 25 IS - 12 SP - 595 EP - 608 KW - pharmacokinetics KW - CYP2D6 KW - ABCG2 KW - simvastatin acid KW - simvastatin KW - pharmacogenomics KW - CYP3A5 KW - SLCO1B1 N2 - Objective

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.

Methods

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.

Results

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 (C max) 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 C max ratio.

Conclusion

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. UR - https://www.ingentaconnect.com/content/wk/phggn/2015/00000025/00000012/art00003 M3 - doi:10.1097/FPC.0000000000000176 UR - https://doi.org/10.1097/FPC.0000000000000176 ER -