simvastatin (simvastatin, Hanmi / simvastatin CR / Simvast CR)

Verification of a Physiologically-based Pharmacokinetic Model for Predicting CYP3A4-mediated Simvastatin and Simvastatin Acid Drug-drug Interactions.

Morse Bridget L BL, Han Bing B, Alberts Jeffrey J JJ, Posada Maria M MM et al.

Simvastatin is a commonly prescribed medication and a sensitive CYP3A4 substrate requiring dosage modification with CYP3A4 precipitants. Unlike other CYP3A4 substrates, grapefruit juice (GFJ) causes the largest increase in simvastatin exposure of any CYP3A4 inhibitor, leading to misunderstanding of simvastatin fraction escaping CYP3A4 metabolism in the gut (Fg, CYP3A4) and fraction metabolized by CYP3A4 in the liver (fm,CYP3A4). Simvastatin is a prodrug that is converted to the active simvastatin acid, though the mechanisms responsible for in vivo simvastatin acid formation are not well-understood. GFJ also decreases the simvastatin acid:simvastatin exposure ratio, suggesting inhibition of simvastatin acid formation. In the current work, we used a static approach to define simvastatin CYP3A4 parameters, using clinical data with index substrate midazolam; estimated simvastatin Fg,CYP3A4 and fm,CYP3A4 were ~ 0.4 and ~ 0.9, respectively. In vitro data assessing the stability of simvastatin and simvastatin acid demonstrated rapid conversion in gastric fluid that was highly pH-dependent. A simvastatin PBPK model was constructed incorporating these CYP3A4 parameters and simvastatin acid formation in stomach, intestine and plasma. The model reproduced the nonlinear pharmacokinetics of simvastatin and CYP3A4 precipitant effects, thus qualifying the model for prediction of CYP3A4-mediated interactions on both simvastatin and simvastatin acid. Simvastatin overall Fg was estimated as ~ 0.2, lower than the Fg,CYP3A4 due to additional intestinal esterase-mediated formation of simvastatin acid. The simvastatin-GFJ effect was explained by inhibition of this intestinal simvastatin acid formation, along with CYP3A4 inhibition. The unique effect of food on the simvastatin acid:simvastatin exposure ratio could also be replicated using this PBPK model.

[Expression of Concern] Simvastatin potentiates doxorubicin activity against MCF-7 breast cancer cells.

Buranrat Benjaporn B, Suwannaloet Wanwisa W, Naowaboot Jarinyaporn J

Protosappanin A Alleviates Atherosclerosis by Regulating the MDM2/GPX4 Axis-Mediated Endothelial Ferroptosis.

Fu Jiamei J, Zhu Lin L, Yang Wenwei W, Li Mengnan M et al.

Endothelial ferroptosis is a crucial pathogenic driver of atherosclerosis (AS) progression. Protosappanin A (PTA), a bioactive compound from Caesalpinia sappan L., protects cardiovascular vessels by regulating ferroptosis. However, whether PTA inhibits AS specifically through suppressing endothelial ferroptosis remains unclear. To address this, ApoE-/- mice were fed a high-fat diet for 16 weeks to induce atherosclerosis, and PTA or simvastatin was administered daily from Week 4 through Week 16 (12 weeks of intervention). PTA markedly reduced aortic plaque area (en face Oil Red O and H&E staining) and improved serum lipid profiles (TG, TC, LDL-C, HDL-C). It also alleviated endothelial injury, evidenced by decreased VCAM-1 and ICAM-1 expression. Mechanistically, PTA ameliorated mitochondrial ferroptosis in endothelial cells, lowered intracellular Fe2+ and lipid peroxidation (MDA, lipid ROS), and restored the expression of GPX4, xCT, and FTH1. Immunofluorescence confirmed that PTA upregulated GPX4 within the aortic endothelium. To explore the underlying mechanism, we performed RNA-seq on ox-LDL-treated HUVECs and integrated the data with ferroptosis-related databases. MDM2 was identified as a key target, which was validated by qPCR and Western blotting. Overexpression of MDM2 activated endothelial ferroptosis and reversed the protective effects of PTA both in vitro and in vivo. Collectively, these findings demonstrate that PTA alleviates AS by suppressing endothelial ferroptosis via the MDM2/GPX4 axis.

Involvement of Protein Kinase C Delta and Monocarboxylate Transporter 4 in the Development of Statin-Induced Cytotoxicity in a Rhabdomyosarcoma-Derived Cell Line.

Okamoto Keisuke K, Matsui Toya T, Kikutani Yurika Y, Ueda Hinata H et al.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, are widely prescribed lipid-lowering agents. Nevertheless, their use is occasionally associated with muscle toxicity, including rhabdomyolysis. Exercise reportedly exacerbates statin-induced muscle injury; however, the underlying mechanisms remain poorly understood. Here, we investigated the role of protein kinase C (PKC) signaling in the development of statin-induced cytotoxicity using a rhabdomyosarcoma-derived cell line (RD cells), with particular emphasis placed on the regulation of monocarboxylate transporter 4 (MCT4), a lactate transporter implicated in intracellular acidification and cytotoxic responses. Treatment with simvastatin, atorvastatin, and fluvastatin reduced RD cell viability in a concentration-dependent manner. Co-treatment with bisindolylmaleimide I (BIM), an inhibitor of PKCα, β, γ, δ, and ε, attenuated statin-induced cytotoxicity and tended to suppress simvastatin-induced MCT4 upregulation. Furthermore, co-treatment with Gö6976, a selective inhibitor of PKCα and β, did not mitigate the simvastatin-induced reduction in cell viability. Small interfering RNA-mediated knockdown of PKCδ significantly rescued simvastatin-induced cytotoxicity. Tamoxifen, a clinically available drug with PKC inhibitory activity, including against the δ isoform, attenuated simvastatin-induced cell injury, paralleling the effects of BIM. Collectively, our findings demonstrate that PKCδ contributes to statin-induced cytotoxicity in rhabdomyosarcoma cells, at least in part by regulating MCT4 expression.