Atorvastatin Metabolite Pattern in Skeletal Muscle and Blood from Patients with Coronary Heart Disease and Statin-Associated Muscle Symptoms.
Trine LauritzenJohn MunkhaugenKari PeersenOscar KristiansenElise SverreShane D NebauerMaja VillsethAnders M AndersenAnja Camilla SvarstadElena Prunés JensenStein BerganEinar HusebyeNils Tore VethePublished in: Clinical pharmacology and therapeutics (2023)
Self-perceived statin-associated muscle symptoms (SAMS) are prevalent, but only a minority is drug-dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in coronary patients with self-perceived SAMS during 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of twelve patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non-SAMS) attended the present follow-up study. All received 7-weeks treatment with atorvastatin 40mg/day followed by 8-weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho >0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T>C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G>A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non-SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.
Keyphrases
- skeletal muscle
- insulin resistance
- cardiovascular disease
- ms ms
- coronary artery disease
- double blind
- chronic kidney disease
- randomized controlled trial
- end stage renal disease
- physical activity
- type diabetes
- risk assessment
- depressive symptoms
- coronary artery
- gene expression
- dna methylation
- combination therapy
- open label
- low density lipoprotein
- replacement therapy
- aortic valve
- preterm birth
- human health
- electronic health record
- protein kinase