Clearance rates of cerivastatin metabolites in a patient with cerivastatin-induced rhabdomyolysis

Ozaki, Hiroshi; Ishikawa, Chikako; Ishii, Toshihiro; Toyoda, Atsushi; Murano, Tadashi; Miyashita, Yoh; Shirai, Kohji

doi:10.1111/j.1365-2710.2005.00633_1.x

Cited by 13 publications

(7 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the novel exonic CYP2C8 variants, V472 fs L494 which results in a modification of the C-terminus, can be expected to exhibit low metabolic activity in vivo because of poor heme incorporation and thus a defective protein. Consequently, carriers of this variant might be expected to experience higher cerivastatin plasma concentrations, as previously reported for the truncated CYP2C8 * 5 variant [32] - which was not found in this study. Allele frequencies of SNPs for CYP2C8 * 3 and CYP2C8 * 4 indicated a slightly lower prevalence in the patient population compared to published MAFs or haplotype frequencies in Caucasian populations, but a statistical analysis could not be performed due to the lack of an appropriate control group.…”

Section: Discussionsupporting

confidence: 62%

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

Kaspera¹,

Naraharisetti²,

Tamraz

et al. 2010

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Cerivastatin, an HMG-CoA reductase inhibitor withdrawn from the market due to serious adverse effects, is metabolized primarily by CYP2C8.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.

show abstract

Section: Discussionsupporting

confidence: 62%

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

Kaspera¹,

Naraharisetti²,

Tamraz

et al. 2010

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…The authors concluded that the 475delA polymorphism, which results in a frameshift and premature protein truncation, was the putative polymorphism causing decreased CYP2C8 metabolizing enzyme activity. In a subsequent analysis, the authors evaluated the cerivastatin metabolite ratios in this patient’s serum, and found the ratio of M-23:M-1 to be lower than in control patients [49]. This finding suggests that decreased metabolism of cerivastatin was evident in this patient, and this may be due to CYP2C8 gene polymorphisms, as previously discussed.…”

Section: Hmg-coa Reductase Inhibitorsmentioning

confidence: 60%

Cytochrome P450 2C8 Pharmacogenetics: A Review of Clinical Studies

2009

View full text Add to dashboard Cite

Cytochrome P450 (CYP) 2C8 is responsible for the oxidative metabolism of many clinically available drugs from a diverse number of drug classes (e.g., thiazolidinediones, meglitinides, NSAIDs, antimalarials and chemotherapeutic taxanes). The CYP2C8 enzyme is encoded by the CYP2C8 gene, and several common nonsynonymous polymorphisms (e.g., CYP2C8*2 and CYP2C8*3) exist in this gene. The CYP2C8*2 and *3 alleles have been associated in vitro with decreased metabolism of paclitaxel and arachidonic acid. Recently, the influence of CYP2C8 polymorphisms on substrate disposition in humans has been investigated in a number of clinical pharmacogenetic studies. Contrary to in vitro data, clinical data suggest that the CYP2C8*3 allele is associated with increased metabolism of the CYP2C8 substrates, rosiglitazone, pioglitazone and repaglinide. However, the CYP2C8*3 allele has not been associated with paclitaxel pharmacokinetics in most clinical studies. Furthermore, clinical data regarding the impact of the CYP2C8*3 allele on the disposition of NSAIDs are conflicting and no definitive conclusions can be made at this time. The purpose of this review is to highlight these clinical studies that have investigated the association between CYP2C8 polymorphisms and CYP2C8 substrate pharmacokinetics and/or pharmacodynamics in humans. In this review, CYP2C8 clinical pharmacogenetic data are provided by drug class, followed by a discussion of the future of CYP2C8 clinical pharmacogenetic research. Keywordsamodiaquine; CYP2C8; cytochrome P450 2C8; human; ibuprofen; NSAID; paclitaxel; repaglinide; thiazolidinedione The field of pharmacogenetics is aimed at understanding how genetic variation contributes to interindividual variability in drug disposition (i.e., pharmacokinetics) and drug response (i.e., pharmacodynamics). In terms of drug disposition, the cytochrome P450 (CYP) metabolizing enzymes are a major area of study, as they catalyze the oxidative metabolism of numerous drugs and endogenous compounds. Enzymes in the CYP2C family (e.g., CYP2C8, CYP2C9, CYP2C18 and CYP2C19) are significant contributors to drug disposition and metabolize 20% of clinically available drugs [1,2]. Recently, the role of the CYP2C8 isoenzyme has garnered considerable interest in the fields of drug metabolism and pharmacogenetics. This is largely a †Author for correspondence: University of Colorado Denver, School of Pharmacy, Department of Pharmaceutical Sciences, 12700 East 19th Avenue, Box C238-P15, Aurora, CO 80045, USA, Tel.: +1 303 724 6126; Fax: +1 303 724 7266; christina.aquilante@ucdenver.edu. For reprint orders, please contact: reprints@futuremedicine.com Financial & competing interests disclosureDr Aquilante currently holds investigator-initiated research grants from the NIH (K23 DK073197), American College of Clinical Pharmacy and Tibotec Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materia...

show abstract

“…As cerivastatin-induced rhabdomyolysis, and more generally statin-induced rhabdomyolysis, is associated with elevated plasma concentration of statins and their active metabolites [10], the reduction in uptake of statins by OATP1B1 variants is expected to lead to higher cerivastatin exposure and an increased risk of rhabdomyolysis. The V174A variant has been associated with an increased risk of simvastatin-induced [5] myopathy and cerivastatin-induced [6] rhabdomyolysis.…”

Section: Discussionmentioning

confidence: 99%

“…Concentrations of substrate and reaction times were selected to be in the linear range of transport. The cerivastatin concentration is also clinically relevant [10,11]. …”

Section: Methodsmentioning

confidence: 99%

OATP1B1-related drug–drug and drug–gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis

Tamraz

Fukushima

Wolfe

et al. 2013

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Objective Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. Methods This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. Results The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. Conclusion Reduced function of OATP1B1 related to genetic variation and drug–drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.

show abstract

Clearance rates of cerivastatin metabolites in a patient with cerivastatin-induced rhabdomyolysis

Cited by 13 publications

References 15 publications

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

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

Cytochrome P450 2C8 Pharmacogenetics: A Review of Clinical Studies

OATP1B1-related drug–drug and drug–gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis

Contact Info

Product

Resources

About