Jangra Aryan, Babu Basuvan, Divakar Selvaraj, Gowramma Byran, Rajan Saveri, Jangra Sonam, Malakar Vishnu
Department of Pharmaceutical Analysis, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India.
Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, India.
Drug Metab Rev. 2025 May 23:1-27. doi: 10.1080/03602532.2025.2508152.
Drug metabolism and pharmacokinetics (DMPK) plays a crucial role in optimizing peroxisome proliferator-activated receptor gamma (PPARγ) modulators by influencing metabolism, therapeutic efficacy, and safety. Rosiglitazone is primarily metabolized by cytochrome 2C8 (CYP2C8) and CYP2C9, with the CYP2C83 polymorphism increasing clearance, reducing efficacy, and altering fluid retention. Troglitazone metabolism via CYP3A4 and CYP2C8 generates a reactive quinone metabolite, depleting glutathione (GSH), elevating mitochondrial oxidative stress, and inducing hepatotoxicity. Glitazones also undergo GSH conjugation through open-ring formation, influencing detoxification and toxicity. Inflammation downregulates CYP enzymes and transporters, altering drug clearance and increasing drug-drug interaction (DDI) risks. Ketoconazole and troleandomycin inhibit rosiglitazone metabolism by 52% and 40%, respectively, while pioglitazone inhibits CYP2C8-mediated arachidonic acid metabolism, impairing renal function. Gemfibrozil further increases pioglitazone's area under the curve (AUC) threefold by inhibiting CYP2C8. Additionally, rosiglitazone modulates OATP1B1, enhancing pravastatin uptake at low concentrations but inhibiting it at higher levels, affecting plasma levels. Troglitazone inhibits organic anion-transporting polypeptide 1B1 (OATP1B1) mediated rosuvastatin uptake, reducing hepatic delivery and efficacy, necessitating strategic drug combinations. Furthermore, new PPARγ modulators are being developed via selective and partial activation to mitigate toxicity, incorporating non-thiazolidinedione scaffolds and optimizing DMPK properties through nanocarriers such as lipid-based nanoparticles. A deeper understanding of these factors is essential for designing next-generation PPARγ-targeted therapeutics, ensuring improved efficacy, reduced toxicity, and enhanced suitability for personalized medicine.
药物代谢与药代动力学（DMPK）通过影响代谢、治疗效果和安全性，在优化过氧化物酶体增殖物激活受体γ（PPARγ）调节剂方面发挥着关键作用。罗格列酮主要由细胞色素2C8（CYP2C8）和CYP2C9代谢，CYP2C83多态性会增加清除率、降低疗效并改变液体潴留。曲格列酮通过CYP3A4和CYP2C8代谢产生一种活性醌代谢物，消耗谷胱甘肽（GSH），增加线粒体氧化应激并诱导肝毒性。格列酮类药物还通过开环形成进行GSH结合，影响解毒和毒性。炎症会下调CYP酶和转运蛋白，改变药物清除率并增加药物相互作用（DDI）风险。酮康唑和醋竹桃霉素分别抑制罗格列酮代谢52%和40%，而吡格列酮抑制CYP2C8介导的花生四烯酸代谢，损害肾功能。吉非贝齐通过抑制CYP2C8使吡格列酮的曲线下面积（AUC）进一步增加三倍。此外，罗格列酮调节有机阴离子转运多肽1B1（OATP1B1），在低浓度时增强普伐他汀的摄取，但在较高浓度时抑制其摄取，影响血浆水平。曲格列酮抑制有机阴离子转运多肽1B1（OATP1B1）介导的瑞舒伐他汀摄取，减少肝脏递送和疗效，因此需要进行策略性药物组合。此外，正在通过选择性和部分激活来开发新的PPARγ调节剂以减轻毒性，采用非噻唑烷二酮支架，并通过脂质纳米颗粒等纳米载体优化DMPK特性。深入了解这些因素对于设计下一代PPARγ靶向治疗药物至关重要，可确保提高疗效、降低毒性并增强个性化医疗的适用性。
