The Influences of SLCO1B1 and ABCB1 Genotypes on the Pharmacokinetics of Simvastatin, in Relation to CYP3A4 Inhibition

Abstract

Aim:To investigate the combined effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin and its active metabolite simvastatin acid, in relation to CYP3A4 inhibition. Methods: We conducted a single-dose pharmacokinetic study of simvastatin in 26 healthy volunteers screened for their SLCO1B1 c.521T>C and ABCB1 c.1236C>T-2677G>T-3435C>T genotypes, with and without amlodipine pretreatment. The genetic effects and drug-interaction effect on simvastatin pharmacokinetic parameters were analyzed using a linear-mixed model. Results: The SLCO1B1 c.521T>C variant significantly increased exposure to simvastatin acid by around 40% (p < 0.05), similar to that caused by the amlodipine pretreatment. The ABCB1 gene showed no influence on exposure to simvastatin or simvastatin acid. Conclusion: Only SLCO1B1, not ABCB1 genotype, is likely to be associated with simvastatin-induced myopathy. SLCO1B1 genotyping may be particularly beneficial in simvastatin users who are co-administered CYP3A4 inhibitors.

Drug–drug–gene interactions and adverse drug reactions

“…For instance, reduced CYP3A4 and SLCO1B1 activities can both result in increased AUC of the substrate drug and a greater harm would be anticipated. Carriers of the TC genotype of SLCO1B1 rs4149056 (T>C) variant who are treated with amlodipine (CYP3A4 inhibitor) experienced a 90% increased simvastatin AUC compared with subjects not treated with amlodipine and wild-type for rs4149056 [87]. A similar scenario was reported with other two case reports (see Supplementary Table 1) [88,89].…”

<b><i>SLCO1B1</i></b> c.521T&gt;C Genotyping in the Austrian Population Using 2 Commercial Real-Time Polymerase Chain Reaction Assays: An Implementation Study

“…The interest in SLCO1B1 as a marker of pharmacogenetics research has increased rapidly during the last decade. In previous studies, the non-coding SLCO1B1 c.521T>C single nucleotide poly- morphism has been shown to be significantly associated with an increased risk of statin-induced adverse reactions [4,5]. Individuals carrying 1 (T/C-heterozygotes) and 2 (C/C-homozygotes) SLCO1B1 c.521C alleles are reported to have a 4-and 16-fold higher risk of dose-dependent myopathy after statin intake compared to T/T-homozygotes, respectively [3,6].…”

MassARRAY Multigene Screening Combined with LDL-C and sdLDL-C Detection for more Favorable Outcomes in type 2 Diabetes Mellitus Therapy

“…Many studies have shown that gene polymorphisms in uence T2DM therapeutic effects [16][17][18][19][20][21][22][23]. SNPs in the HTR3B, HTR7 or ABCB1 genes were associated with myalgia or liver injury [16,22].…”

“…APOE and HMGCR mutations were associated with LDL-C levels [17,20]. CETP, KIF6, SLCO1B1, and CYP2C9*3 were related to the statin effect [18,19,21,23]. To check genetic polymorphisms in Chinese T2DM patients, HTR3B (rs2276307, A > G), APOE (rs7412, c.526C > T), APOE (rs429358, c.388T > C), CYP2C9*3 (rs1057910, c.1075A > C), KIF6 (rs20455, c.2155T > C), HMGCR (rs17238540, T > G), HMGCR (rs17244841, A > T), ABCB1 (rs2032582, c.2677G > T/A), HTR7 (rs1935349, C > T), SLCO1B1 (rs4149056, c.521T > C), and CETP (rs708272, G > A) were detected by the MassARRAY system before patients underwent statin therapy ( Fig.…”