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Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage

Wilke, Russell A.a b; Moore, Jason H.c; Burmester, James K.a

Pharmacogenetics and Genomics:
Original Articles
Abstract

Atorvastatin is metabolized through enzymes encoded by members of the cytochrome P-450 (CYP) 3A gene family. Some patients who take atorvastatin along with concomitant medications known to inhibit CYP3A enzyme activity (e.g. itraconazole) develop rhabdomyolysis secondary to a severe drug-induced myopathy. The present study aimed to characterize the relationship between CYP3A gene polymorphisms and atorvastatin-induced muscle damage in the context of concomitant medication. The study employed a retrospective case–control (n=137) design. Study subjects were recruited from the general patient population served by Marshfield Clinic, a large horizontally integrated multispecialty group practice located in central Wisconsin, and case assignment was based upon both subjective (myalgia) and objective inclusion criteria [elevated serum creatine kinase (CK) levels]. The primary outcome was the relationship between serum CK level and CYP3A genotype. CYP3A genotype was not associated with an increased risk for the development of atorvastatin-induced muscle damage. CYP3A4*1B and CYP3A5*3 allele frequencies were similar in cases (n=68) and controls (n=69). Conversely, CYP3A genotype was associated with an increased severity of atorvastatin-induced muscle damage. An association was identified between the non-functional CYP3A5*3 allele and the magnitude of serum CK elevation in case patients experiencing myalgia. Patients who were homozygous for CYP3A5*3 demonstrated greater serum CK levels than patients who were heterozygous for CYP3A5*3, when concomitant lipid-lowering agents were sequentially removed from the analysis (P=0.025 without gemfibrozil, P=0.010 without gemfibrozil and niacin). The study demonstrates that patients who develop myalgia while taking atorvastatin are more likely to experience a greater degree of muscle damage if they express two copies of CYP3A5*3.

Author Information

aCenter for Human Genetics, Marshfield Clinic Research Foundation

bDepartment of Internal Medicine, Marshfield Clinic, Marshfield, Wisconsin, USA

cComputational Genetics Laboratory, Department of Genetics, Dartmouth Medical School, Lebanon, New Hampshire, USA

Sponsorship: This study was supported in part by the Marshfield Clinic Research Foundation (R.A.W.).

Correspondence and requests for reprints to Russell A. Wilke, Center for Human Genetics, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449, USA

Tel: +1 715 387 9433; fax: +1715 3894950;

e-mail: wilke.russell@mcrf.mfldclin.edu

Received 2 December 2004 Accepted 22 March 2005

© 2005 Lippincott Williams & Wilkins, Inc.