The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6

Abstract

Aims To identify the cytochrome P450 (CYP) isoforms responsible for the metabolism of simvastatin hydroxy acid (SVA), the most potent metabolite of simvastatin (SV). Methods The metabolism of SVA was characterized in vitro using human liver microsomes and recombinant CYPs. The effects of selective chemical inhibitors and CYP antibodies on SVA metabolism were assessed in human liver microsomes. Results In human liver microsomes, SVA underwent oxidative metabolism to three major oxidative products, with values for Km and V max ranging from about 50 to 80 m M and 0.6 to 1.9 nmol min -1 mg -1 protein, respectively. Recombinant CYP3A4, CYP3A5 and CYP2C8 all catalysed the formation of the three SVA metabolites, but CYP3A4 was the most active. CYP2D6 as well as CYP2C19, CYP2C9, CYP2A6, CYP1A2 did not metabolize SVA. Whereas inhibitors that are selective for CYP2D6, CYP2C9 or CYP1A2 did not significantly inhibit the oxidative metabolism of SVA, the CYP3A4/5 inhibitor troleandomycin markedly (about 90%) inhibited SVA metabolism. Quercetin, a known inhibitor of CYP2C8, inhibited the microsomal formation of SVA metabolites by about 25-30%. Immunoinhibition studies revealed 80-95% inhibition by anti-CYP3A antibody, less than 20% inhibition by anti-CYP2C19 antibody, which cross-reacted with CYP2C8 and CYP2C9, and no inhibition by anti-CYP2D6 antibody. Conclusions The metabolism of SVA in human liver microsomes is catalysed primarily ( ≥ 80%) by CYP3A4/5, with a minor contribution ( £ 20%) from CYP2C8. CYP2D6 and other major CYP isoforms are not involved in the hepatic metabolism of SVA.

Clinical implications of pharmacogenomics of statin treatment

“…Variation in CYP2D6 has been associated with decreased adherence to simvastatin therapy, although the metabolic significance of this enzyme in simvastatin clearance is under debate. 23,25 The presence of the e4 allele of ApoE is associated with decreased adherence. 67 A case of rhabdomyolysisinduced death from cerivastatin exposure may have been caused by a loss of function mutation in CYP2C8 resulting in increased systemic exposure.…”

“…[21][22][23] These data are further complicated by conflicting reports as to the significance of CYP2D6 metabolism in simvastatin clearance. [24][25][26] Conflicting conclusions from individual studies are largely due to limited sample size as underpowered studies are less likely to yield reproducible results. Two studies have recently appeared that attempted to address this issue: the Pravastatin Inflammation/CRP Evaluation (PRINCE) study, which examined associations of pravastatin efficacy with variation across 10 candidate genes in 1536 subjects; the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS), which examined associations between variation in 14 candidate genes and statin efficacy in 3916 subjects on various statins, half of whom were administered atorvastatin.…”

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

“…Simvastatin is primarily metabolized in the liver by two separate metabolic pathways. In humans, the oxidative biotransformation of simvastatin is mediated primarily by CYP3A4 [10] . In the other primary route, the inactive lactone prodrug is hydrolyzed to the pharmacologically active simvastatin acid by carboxylesterases and non-enzymes.…”

“…In the other primary route, the inactive lactone prodrug is hydrolyzed to the pharmacologically active simvastatin acid by carboxylesterases and non-enzymes. The oxidative metabolism of simvastatin acid is catalyzed primarily by CYP3A4 [10] . Additionally, simvastatin and its hydrolysate simvastatin acid are substrates of organic anion transporting polypeptide 1B1 (OATP1B1/Oatp2) [11][12][13][14] , an influx transporter expressed on the sinusoidal membrane of hepatocytes.…”

Pediatric Statin Administration: Navigating a Frontier with Limited Data

“…95,[150][151][152] In the presence of the CYP3A4/5 inhibitor troleandomycin, simvastatin acid metabolism is decreased by 90%. 150 When administered concurrently with the CYP3A4 inhibitor itraconazole, 15-to 19-fold increases are observed in simvastatin and lovastatin AUCs.…”