Rhabdomyolysis Associated with Cerivastatin: Six Cases within 3 Months at One Hospital

Lucas, Robert A.; Weathersby, B. Blake; Rocco, Vito K.; Pepper, Jonathan; Butler, Kerry L.

doi:10.1592/phco.22.9.771.34071

Cited by 10 publications

(5 citation statements)

References 9 publications

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“…The increased risk of rhabdomyolysis associated with cerivastatin was not identified in premarketing clinical trials, but became apparent on post‐marketing surveillance (8, 9). Clinical features of our case coincided with typical rhabdomyolysis.…”

Section: Resultsmentioning

confidence: 99%

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

Ozaki¹,

Ishikawa²,

Ishii³

et al. 2005

J Clin Pharm Ther

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We report on a patient who developed acute rhabdomyolysis after taking cerivastatin. A 74-year-old hypercholestrerolaemic woman taking cerivastatin (0.15 mg/day) for 22 days complained of general muscle weakness and muscle pain. Her serum creatinine phosphokinase level was 19,190 IU/L. Serum myoglobin was over 3000 ng/mL. Serum concentration of cerivastatin at 6 h after taking the last dose (0.15 mg) was 8062.5 ng/L, which was almost 5.7 times higher than that of normal persons. The serum concentration of cerivastatin showed that the half-life of cerivastatin in this patient was 22.4 h, compared with 2.4 h for normal controls. Cerivastatin is catabolized by cytochrome P450, 3A4 and 2C8 to M-1, and by 2C8 to M-23. The ratio of M-23 to M-1 in her serum was much lower than that of control persons (0.64 vs. 2.08). She had previously taken simvastatin which is metabolized by CYP3A4, without any sign and symptoms of rhabdomyolysis. These results suggest that the slowed clearance of cerivastatin in this patient might have been compounded by cytochrome P450, 2C8 dysfunction.

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Section: Resultsmentioning

confidence: 99%

“…However, adverse reactions involving skeletal muscles range from mild myopathy to rhabdomyolysis (6, 7). Rhabdomyolysis with cerivastatin administration have been reported from all over the world (8, 9). Generally, rhabdomyolysis seems to occur with large doses of statins.…”

Section: Introductionmentioning

confidence: 99%

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

Ozaki¹,

Ishikawa²,

Ishii³

et al. 2005

J Clin Pharm Ther

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“…CYP3A4 contributes to a minor extent in the formation of M-1 [42]. In 2001, cerivastatin was withdrawn from the worldwide market due to a higher incidence of rhabdomyolysis compared with other statins [44,45]. Rhabdomyolysis is the consequence of excessive muscle breakdown that results in acute renal failure, cardiac complications and compression of the nerves and blood vessels [46].…”

Section: Hmg-coa Reductase Inhibitorsmentioning

confidence: 99%

Cytochrome P450 2C8 Pharmacogenetics: A Review of Clinical Studies

2009

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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...

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“…Although the statins have been proven relatively safe, the recent withdrawal of cerivastatin owing to 52 cases of fatal rhabdomyolysis, 12 of which involved concomitant use of gemfibrozil, has cast doubt on the world's most widely prescribed lipid‐lowering agents ( Furberg & Pitt, 2001 ; Lucas et al ., 2002 ). Thus, there has been an explosion of studies describing the pleiotropic effects of the statins, and these studies are the subject of intense and justified interest.…”

Section: Discussionmentioning

confidence: 99%

Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo

O'Meara

Kinsella

2004

British J Pharmacology

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1 Prostacyclin plays a central role within the vasculature. We have previously established that the prostacyclin receptor (IP) undergoes isoprenylation, a lipid modification obligate for its function. The aim of the current study was to investigate the effect of the hydroxy methyl glutaryl co-enzyme A reductase inhibitor atorvastatin on signalling and function of the IP expressed in mammalian whole cells and in platelets isolated from patients undergoing therapeutic intervention with atorvastatin. 2 Initially, the effect of atorvastatin on signalling by the human (h) and mouse (m) IP overexpressed in human embryonic kidney 293 cells and the hIP endogenously expressed in human erythroleukaemic 92.1.7 cells was investigated. Atorvastatin significantly reduced IP-mediated cAMP generation (IC 50 6.6-11.1 mM) and [Ca 2 þ ] i mobilization (IC 50 7.2-16.4 mM) in a concentration-dependent manner, but had no effect on signalling by the nonisoprenylated b 2 adrenergic receptor or the a or b isoforms of the human thromboxane A 2 receptor (TP). 3 Moreover, atorvastatin significantly reduced IP-mediated crossdesensitization of signalling by TPa (IC 50 10.4 mM), but not by TPb. 4 In contrast to the whole-cell data, atorvastatin therapy did not interfere with IP-mediated cAMP generation or IP-induced inhibition of TP-mediated aggregation of platelets isolated from human volunteers undergoing therapeutic intervention with atorvastatin (10-80 mg per daily dose).

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Rhabdomyolysis Associated with Cerivastatin: Six Cases within 3 Months at One Hospital

Cited by 10 publications

References 9 publications

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

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

Cytochrome P450 2C8 Pharmacogenetics: A Review of Clinical Studies

Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo

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