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 -