Studies of Pharmacokinetics in Beagle Dogs and Drug-drug Interaction Potential of a Novel Selective ZAK Inhibitor 3h for Hypertrophic Cardiomyopathy Treatment

Publication date: Available online 26 April 2019Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Weifan Jiang, Lan Ding, Tianming Dai, Jiayin Guo, Renke Dai, Yu ChangAbstractOverexpression of leucine-zipper and sterile-α motif kinase (ZAK) in heart has been closely associated with the development of hypertrophic cardiomyopathy (HCM). N-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl) benzene-sulfonamides, novel highly selective ZAK inhibitors, had exhibited reasonable orally therapeutic effects on HCM in spontaneous hypertensive rat models. In the present study, a rapid and sensitive HPLC-MS/MS method for determining ZAK inhibitor 3 h in beagle dog plasma was developed and validated. Meanwhile, the pharmacokinetics in beagle dog and drug-drug interaction potential of 3 h had been conducted. The pharmacokinetic results showed that the absolute oral bioavailability for 3 h in beagle dogs was determined to be 61.9%, which was significantly higher than that in the previous determination in Spragur-Dawley rats (F = 20%). The Cytochrome P450 enzymes and P-glycoprotein mediated drug-drug interactions by 3 h were also investigated using dog and human liver microsomes and Caco-2 cells. The results demonstrated that only CYP2C9 was obviously inhibited (IC50 = 1.66 μM). Besides, 3 h could significantly decrease digoxin efflux ratio in Caco-2 experiments in a dose-dependent manner (IC50 = 13.3 μM). Considering 3 h strongly suppressed the ZAK k...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research