Pharmacokinetics of the bradykinin antagonist derivative 1,4-benzodiazepin-2-one in the experiment

Introduction. The 1,4-benzodiazepin-2-one derivative (codenamed – PAV-0056), in a wide range of low doses 0.1–10 mg/kg has a pronounced analgesic effect as bradykinin receptor type 1 antagonist. Preclinical study of the pharmacokinetics of a new potential analgesic with different routes of administration in appropriate doses seems to be relevant. Aim. To evaluate the pharmacokinetic parameters, bioavailability and transmembrane transport of the 1,4-benzodiazepin-2-one derivative PAV-0056. Materials and methods. PAV-0056 at doses of 0.1, 1 and 10 mg/kg was administered in a 1% aqueous solution of polyvinylpyrrolidone into the stomach and vein of male Sprague Dawley rats (age 1.5–3 months) weighing 250–300 g. We determined the plasma concentration of PAV-0056 in the blood of rats at discrete time intervals using mass spectrometry. The pharmacokinetic parameters and absolute bioavailability of PAV-0056 were studied. The permeability of PAV-0056 through a cell monolayer was studied on a 21-day cell culture originated from of colorectal carcinoma (CaCO-2). Results. The absolute bioavailability of the 1,4-benzodiazepin-2-one derivative PAV-0056 after administration into the stomach of rats at a dose of 0.1 mg/kg is 10.1 ± 6.1%, at a dose of 1 mg/kg – 2.2 ± 0.1%, at a dose of 10 mg/kg – 6.4 ± 0.8%. Systemic exposure AUC and maximum plasma concentration Cmax change linearly with increasing dose of PAV-0056 from 0.1 to 10 mg/kg (coefficients of determination R2 are 0.9767 and 0.9976, respectively). PAV-0056 is absorbed from the small intestine within 1 h and eliminated from plasma within 5 h (the lower limit of quantification of PAV-0056 in plasma is 0.1 ng/ml). After intravenous administration, PAV-0056 is eliminated within 0.5 h. The analgesic has a total clearance (ClT) of 83.16 l/kg/h and is not a P-glycoprotein substrate. Conclusion. The lipophilic derivative of 1,4-benzodiazepin-2-one, PAV-0056 after administration into the stomach is absorbed from the small intestine by passive diffusion with a bioavailability of no more than 10.1 ± 6.1%. Linear pharmacokinetics and no interaction with P-glycoprotein allow PAV-0056 to be positioned as a non-opioid analgesic with a good safety profile.