Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage.
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.
Wilke
Russell A
RA
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield Clinic, Marshfield, Wisconsin, USA. wilke.russell@mcrf.mfldclin.edu
Moore
Jason H
JH
Burmester
James K
JK
D000328:Adult; D000924:Anticholesteremic Agents / Q000009:adverse effects*; D000069059:Atorvastatin; D001483:Base Sequence; D016022:Case-Control Studies; D003402:Creatine Kinase / Q000097:blood; D017931:DNA Primers; D005838:Genotype; D006538:Heptanoic Acids / Q000009:adverse effects*; D006801:Humans; D009135:Muscular Diseases / Q000139:chemically induced*; D011758:Pyrroles / Q000009:adverse effects*; D012307:Risk Factors
D000924:Anticholesteremic Agents; D017931:DNA Primers; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D003402:Creatine Kinase