Atorvastatin Metabolite Pattern in Skeletal Muscle and Blood from Patients with Coronary Heart Disease and Statin‐Associated Muscle Symptoms

Author:

Lauritzen Trine12ORCID,Munkhaugen John13,Peersen Kari4,Kristiansen Oscar13ORCID,Sverre Elise13,Nebauer Shane D.5ORCID,Villseth Maja6,Andersen Anders M.7ORCID,Svarstad Anja Camilla7,Jensen Elena Prunés8,Bergan Stein79ORCID,Husebye Einar1,Vethe Nils Tore7ORCID

Affiliation:

1. Department of Medicine, Vestre Viken Trust Drammen Hospital Drammen Norway

2. Department of Clinical Medicine University of Oslo Oslo Norway

3. Department of Behavioural Medicine, Faculty of Medicine University of Oslo Oslo Norway

4. Department of Cardiology Vestfold Hospital Trust Tønsberg Norway

5. Department of Orthopedic Surgery Vestfold Hospital Trust Tønsberg Norway

6. Department of Neurology, Vestre Viken Trust Drammen Hospital Drammen Norway

7. Department of Pharmacology Oslo University Hospital Oslo Norway

8. Department of Laboratory Medicine Vestre Viken Hospital Trust Drammen Norway

9. Department of Pharmacy University of Oslo Oslo Norway

Abstract

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 patients with coronary disease and self‐perceived SAMS during 7 weeks of double‐blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 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 of treatment with atorvastatin 40 mg/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.

Publisher

Wiley

Subject

Pharmacology (medical),Pharmacology

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