Hermann Monica, Bogsrud Martin P, Molden Espen, Asberg Anders, Mohebi Beata U, Ose Leiv, Retterstøl Kjetil
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, and Lipid Clinic, Rikshospitalet, Norway.
Clin Pharmacol Ther. 2006 Jun;79(6):532-9. doi: 10.1016/j.clpt.2006.02.014.
The most serious side effect from statin treatment is myopathy, which may proceed to rhabdomyolysis. This is the first study to investigate whether the pharmacokinetics of either atorvastatin or its metabolites, or both, is altered in patients with atorvastatin-related myopathy compared with healthy controls.
A 24-hour pharmacokinetic investigation was performed in 14 patients with atorvastatin-related myopathy. Relevant polymorphisms in SLCO1B1 (encoding organic anion transporting polypeptide 1B1), MDR1/ABCB1 (encoding P-glycoprotein), and CYP3A5 (encoding cytochrome P450 3A5) were determined. Data from 15 healthy volunteers were used as controls.
No statistically significant difference in systemic exposure of atorvastatin was observed between the 2 groups. However, patients with atorvastatin-related myopathy had 2.4-fold and 3.1-fold higher systemic exposures of the metabolites atorvastatin lactone (P<.01) and p-hydroxyatorvastatin (P<.01), respectively, compared with controls. There were no differences in frequencies of SLCO1B1, MDR1, and CYP3A5 polymorphisms between the 2 groups.
This study disclosed a distinct difference in the pharmacokinetics of atorvastatin metabolites between patients with atorvastatin-related myopathy and healthy control subjects. These results are of importance in the further search for the mechanism of statin-induced myopathy.
他汀类药物治疗最严重的副作用是肌病，可能进展为横纹肌溶解。这是第一项研究，旨在调查与健康对照相比，阿托伐他汀相关肌病患者中阿托伐他汀及其代谢物或两者的药代动力学是否发生改变。
对14例阿托伐他汀相关肌病患者进行了24小时药代动力学研究。测定了SLCO1B1（编码有机阴离子转运多肽1B1）、MDR1/ABCB1（编码P-糖蛋白）和CYP3A5（编码细胞色素P450 3A5）的相关多态性。15名健康志愿者的数据用作对照。
两组间阿托伐他汀的全身暴露量无统计学显著差异。然而，与对照组相比，阿托伐他汀相关肌病患者的代谢物阿托伐他汀内酯（P<0.01）和对羟基阿托伐他汀（P<0.01）的全身暴露量分别高2.4倍和3.1倍。两组间SLCO1B1、MDR1和CYP3A5多态性的频率无差异。
本研究揭示了阿托伐他汀相关肌病患者与健康对照者在阿托伐他汀代谢物药代动力学方面存在明显差异。这些结果对于进一步探索他汀类药物诱导肌病的机制具有重要意义。
