Ferri Nicola, Colombo Elisa, Corsini Alberto
Department of Medicine, University of Padova, 35100 Padua, Italy.
Veneto Institute of Molecular Medicine, 35129 Padua, Italy.
Pharmaceutics. 2024 Oct 26;16(11):1371. doi: 10.3390/pharmaceutics16111371.
Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug-drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid-CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid-CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein-cholesterol (LDL-C) (20-25%), non-high-density lipoprotein-cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid-glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications.
贝派地酸是一种新药，无论是作为单一疗法还是与现有的降脂疗法联合使用，都能改善胆固醇水平的控制，并在心血管疾病患者中显示出临床疗效。因此，患有合并症且接受多种疗法的患者可能适合使用贝派地酸，从而面临药物相互作用（DDIs）的潜在问题。贝派地酸是一种前药，口服给药，每日固定剂量为180毫克。二羧酸通过与辅酶A（CoA）结合而被酶激活，形成药理活性硫酯（贝派地酸-CoA）。这个过程由超长链酰基辅酶A合成酶1（ACSVL1）催化，该酶几乎只在肝脏水平表达。贝派地酸-CoA是ATP柠檬酸裂解酶（ACL）的强效选择性抑制剂，ACL是胆固醇和脂肪酸生物合成途径中的关键酶。该药物可降低高胆固醇血症或混合性血脂异常患者的低密度脂蛋白胆固醇（LDL-C）（20%-25%）、非高密度脂蛋白胆固醇（HDL-C）（19%）、载脂蛋白B（apoB）（15%）和总胆固醇（16%）。该药物具有良好的药代动力学特征。贝派地酸及其代谢产物不是参与药物代谢的细胞色素P450（CYP450）的底物或抑制剂/诱导剂。另一方面，贝派地酸葡糖醛酸是有机阴离子转运体3（OAT3）的底物。贝派地酸及其葡糖醛酸是OAT2、OAT3以及有机阴离子转运多肽1B1（OATP1B1）和1B3（OATP1B3）的弱抑制剂。因此，贝派地酸可能会抑制（引发药物相互作用的药物）OATP1B1/3底物药物的肝脏摄取以及OAT2和OAT3底物的肾脏清除，并且可能受到（药物相互作用中的受害者）OAT3转运体抑制剂的影响，从而减少其肾脏清除。基于这些药理学特性，在此我们描述贝派地酸与同时使用的药物之间潜在的药物相互作用以及可能的临床意义。
