Different Effects of the ABCG2 C.421C>A SNP on the Pharmacokinetics of Fluvastatin, Pravastatin and Simvastatin

Abstract

Genetic variability in ABCG2 markedly affects the pharmacokinetics of fluvastatin and simvastatin lactone, but has no significant effect on pravastatin or active simvastatin acid. Genotyping for ABCG2 in addition to SLCO1B1 and ABCB1 polymorphisms could help in predicting statin pharmacokinetics when selecting a statin and its dose for an individual patient.

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

“…Both clinical trials and animal experiments have demonstrated that DM may alter the pharmacokinetic behaviors of some drugs via regulating the expressions and activities of cytochrome P450s (CYP450s) and drug transporters in the liver [16][17][18][19][20][21][22] . Breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) have also been reported to mediate statin transport [11,23,24] . All of these results suggest that diabetes modifies the disposition of simvastatin as a result of the alterations of these metabolic enzymes and drug transporters.…”

Screening study for genetic polymorphisms affecting pharmacokinetics of simvastatin

“…It reduces low density lipoprotein (LDL) cholesterol concentrations by inhibiting cholesterol synthesis in the liver. [14] Many clinical trials have shown that simvastatin reduces the risk of death and other complications in patients with chronic heart disease. [15][16][17] Recently, many studies have reported a relationship between genetic polymorphisms and simvastatin PK.…”

Pediatric Statin Administration: Navigating a Frontier with Limited Data

“…168 Conversely, the ABCG2 c.421C>A variant, which has been associated with transport activity in vitro, 169 appears to increase the exposure of atorvastatin, fluvastatin, simvastatin lactone, and rosuvastatin by 72%, 72%, 111%, and 144%, respectively, in subjects with the AA genotype compared to those in patients with the wild-type CC genotype. 75,170 Note that this genotype does not appreciably impact the pharmacokinetics of simvastatin acid or pravastatin. 170 As discussed in Absorption above, pravastatin is subject to MRP2-mediated transport in vitro at the level of the enterocyte and hepatocyte.…”

“…75,170 Note that this genotype does not appreciably impact the pharmacokinetics of simvastatin acid or pravastatin. 170 As discussed in Absorption above, pravastatin is subject to MRP2-mediated transport in vitro at the level of the enterocyte and hepatocyte. [69][70][71] In vivo, the ABCC2 c.1446C>G variant decreases the exposure of pravastatin (AUC, −68%) compared to wild-type controls secondary to a "gain of function" mutation.…”