Kura Raghunandan Reddy, Kilari Eswar Kumar, Shaik Mastan
Pharmacology Division, Andhra University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India.
Medical Services, Troikaa Pharmaceuticals Ltd., Ahmedabad, Gujarat, India.
PeerJ. 2018 May 22;6:e4798. doi: 10.7717/peerj.4798. eCollection 2018.
Concomitant drug administration is a general phenomenon in patients with chronic diseases such as diabetes mellitus. Among the currently available oral antidiabetic drugs, gliclazide is a commonly prescribed drug considering its multiple benefits in diabetic patients. Aprepitant is a commonly prescribed antiemetic drug which is mainly metabolized by CYP3A4, reported to have modest inductive and inhibitory effects on CYP2C9 and CYP3A4, respectively. Since gliclazide is metabolized by CYP2C9 (major) and CYP3A4 (minor), it is very difficult to predict the influence of aprepitant and its metabolic interaction with gliclazide. Considering the complexity associated with the combination of aprepitant and gliclazide, this study was designed to evaluate the influence of aprepitant on the pharmacodynamics (PD) and pharmacokinetics (PK) of gliclazide in animal models.
The PD interaction studies were conducted in both rodent (normal and alloxan-induced diabetic rats) and non-rodent (rabbits) animal models ( = 6) while the PK interaction study was conducted in normal rabbits ( = 6). An extrapolated human therapeutic oral dose of gliclazide, aprepitant and their combination were administered to rats and rabbits with 7 days washout between each treatment. For the multiple-dose interaction study, the same groups were administered with an interacting drug (aprepitant) for 7 days and then the combination of aprepitant and gliclazide on the 8th day. From the collected animal blood samples, blood glucose (by Glucose-Oxidase/Peroxidase method), insulin (by ELISA method) and gliclazide concentration levels (by HPLC method) were determined. Non-compartmental PK analysis was conducted by Phoenix WinNonlin software to determine the PK parameters of gliclazide. Statistical analysis was performed by student's paired -test.
The pharmacodynamic activity (blood glucose reduction and insulin levels) of gliclazide was significantly ( < 0.05) influenced by aprepitant in normal and diabetic condition without any convulsions in animals. There was a significant ( < 0.05) increase in concentration levels and Area Under the Curve of gliclazide while significant ( < 0.05) decrease in clearance levels of gliclazide in rabbits. The PK interaction with gliclazide is relatively more with the multiple dose treatment of aprepitant over single dose treatment.
In combination, aprepitant significantly influenced the pharmacodynamic activity of gliclazide in animal models. Considering this, care should be taken when this combination is prescribed for the clinical benefit in diabetic patients.
合并用药在糖尿病等慢性病患者中是普遍现象。在目前可用的口服抗糖尿病药物中，格列齐特因其对糖尿病患者有多种益处而成为常用处方药。阿瑞匹坦是一种常用的止吐药，主要通过CYP3A4代谢，据报道分别对CYP2C9和CYP3A4有适度的诱导和抑制作用。由于格列齐特由CYP2C9（主要）和CYP3A4（次要）代谢，很难预测阿瑞匹坦的影响及其与格列齐特的代谢相互作用。考虑到阿瑞匹坦与格列齐特联合使用的复杂性，本研究旨在评估阿瑞匹坦对动物模型中格列齐特的药效学（PD）和药代动力学（PK）的影响。
在啮齿动物（正常和四氧嘧啶诱导的糖尿病大鼠）和非啮齿动物（兔子）动物模型（每组n = 6）中进行药效学相互作用研究，而在正常兔子（每组n = 6）中进行药代动力学相互作用研究。将格列齐特、阿瑞匹坦及其组合的推算人体治疗口服剂量给予大鼠和兔子，每次治疗之间有7天的洗脱期。对于多剂量相互作用研究，相同的组给予相互作用药物（阿瑞匹坦）7天，然后在第8天给予阿瑞匹坦和格列齐特的组合。从采集的动物血样中，测定血糖（采用葡萄糖氧化酶/过氧化物酶法）、胰岛素（采用ELISA法）和格列齐特浓度水平（采用HPLC法）。通过Phoenix WinNonlin软件进行非房室药代动力学分析，以确定格列齐特的药代动力学参数。采用学生配对t检验进行统计分析。
在正常和糖尿病状态下，阿瑞匹坦对格列齐特的药效学活性（血糖降低和胰岛素水平）有显著影响（P < 0.05），且动物无惊厥发生。兔子体内格列齐特的浓度水平和曲线下面积显著增加（P < 0.05），而清除率显著降低（P < 0.05）。与单剂量治疗相比，阿瑞匹坦多剂量治疗与格列齐特的药代动力学相互作用相对更大。
联合使用时，阿瑞匹坦在动物模型中显著影响格列齐特的药效学活性。考虑到这一点，在为糖尿病患者开具此联合用药以获得临床益处时应谨慎。
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