A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

Abstract

A hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patient's DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patient's children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.

Inhibition of Hepatic Organic Anion-Transporting Polypeptide by RNA Interference in Sandwich-Cultured Human Hepatocytes: An In Vitro Model to Assess Transporter-Mediated Drug-Drug Interactions

“…The two primary metabolites of cerivastatin, M1 and M23, are produced via demethylation and hydroxylation pathways, respectively (Mück, 2000;Prueksaritanont et al, 2002). In human liver, cerivastatin was actively taken up into hepatocytes by OATP transporters (Ishikawa et al, 2004). Several clinical and in vitro studies have been performed to investigate the mechanisms of cerivastatin DDIs between cerivastatin and gemfibrozil (Backman et al, 2002;Shitara et al, 2004).…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Individuals with variants in the CYP2C8 gene may have been predisposed to this side effect. However, this theory is hypothetical, and there seems to be only one case report of rhabdomyolysis in association with CYP2C8 variants (CYP2C8*5/*5) (Ishikawa et al, 2004).…”

Clinical implications of pharmacogenomics of statin treatment

“…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. 117 The SLCO1B1*15 haplotype, causing decreased hepatic uptake of pravastatin, is over-represented in subjects presenting with rhabdomyolysis. 118 Novel methods of recruitment will be necessary to compile populations better served to address the question of genetic variation in statin-induced ADR.…”