Cerivastatin in vitro metabolism by CYP2C8 variants found in patients experiencing rhabdomyolysis

Abstract

Cerivastatin, an HMG-CoA reductase inhibitor withdrawn from the market due to serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered cerivastatin pharmacokinetics due to gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in cerivastatin clearance. However, the effect of CYP2C8 genetic variation on cerivastatin metabolism has not been fully elucidated. In this study, patients (n=126) with confirmed cases of rhabdomyolysis following cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of cerivastatin by the discovered CYP2C8 variants was investigated. In this unique patient population, twelve novel SNPs were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promotor located deletion (-635_-634delTA) was tightly linked to CYP2C8*3. Seven exonic variants were heterologously expressed in E.coli to assess their influence on cerivastatin metabolism. Recombinant CYP2C8.3 and CYP2C8.4 displayed an increase in cerivastatin metabolic clearance up to six fold compared to the wild type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C8*3 and CYP2C8*4 alleles exhibited a 2 to 14-fold increase in normalized cerivastatin intrinsic clearance, compared to microsomes from livers carrying only the wild type allele. This gain or loss of catalytic function could certainly alter cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…Similarly, the intrinsic clearances of arachidonic acid and tanshinol borneol ester appeared to be lower by CYP2C8.2 than by CYP2C8.1, but the differences were not statistically significant (Dai et al, 2001;Liu et al, 2010a). On the other hand, the intrinsic clearances for cerivastatin M-23 and M-1 metabolite formation and Rand S-ibuprofen hydroxylations have been nonsignificantly higher in CYP2C8.2 than in CYP2C8.1 (Kaspera et al, 2010;Yu et al, 2013b). Both the SIFT or Polyphen in silico prediction algorithms suggest that the amino acid change in CYP2C8.2 is deleterious for CYP2C8 activity (Table 5).…”

“…Similarly, the intrinsic clearances of repaglinide and R-and S-ibuprofen have been 20, 50, and 53% lower by CYP2C8.4 than by CYP2C8.1, respectively (Yu et al, 2013b). On the other hand, the intrinsic clearances of cerivastatin to M-23 and M-1 were about 2-to 2.5-fold higher by CYP2C8.4 than by CYP2C8.1 (Kaspera et al, 2010). The intrinsic clearance of tanshinol borneol ester was not significantly different between CYP2C8.4 and CYP2C8.1 (Liu et al, 2010a).…”

“…Parent cerivastatin (acid) is metabolized by CYP2C8 and CYP3A4, whereas cerivastatin lactone is predominantly metabolized by CYP3A4 (Boberg et al, 1997;Wang et al, 2002;Fujino et al, 2004). The formation of the major metabolite of cerivastatin, 6-hydroxycerivastatin (M-23), is primarily mediated by CYP2C8, whereas both CYP2C8 and CYP3A4 produce demethylcerivastatin (M1) Kaspera et al, 2010). The notorious in vivo interaction between gemfibrozil and cerivastatin is discussed in section VI.C.4.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…For instance, gain or loss of catalytic function in the CYP2C8 gene causes an alteration of cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme, altering cerivastatin pharmacokinetics and influencing, at least in part, the susceptibility to the development of myotoxicity (Kaspera et al, 2010). Conversely, a recently discovered polymorphism of CYP3A5 gene seems not to be an important factor in the modification of atorvastatin disposition and pharmacodynamics in humans (Park et al, 2008).…”

PharmGKB summary

“…Other studies have found no influence of CYP2C8*3 on paclitaxel metabolism [80,87,88]. For some substrates, such as pioglitazone, repaglinide, and cerivastatin, CYP2C8*3 has been associated with increased metabolism [84,89,90]. It has also been shown that CYP2C8*3 exhibits higher overall activity than CYP2C8*1 in the presence of the redox partners, cytochrome b5 and cytochrome P450 reductase [91].…”