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

I n t r o d u c t i o n . 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.
A i m . To evaluate the pharmacokinetic parameters, bioavailability and transmembrane transport of the 1,4-benzodiazepin-2-one derivative PAV-0056.
M a t e r i a l s  a n d  m e t h o d s . 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).
R e s u l t s . 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 C_max 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. After intravenous administration, PAV-0056 is eliminated within 0.5 h. The analgesic has a total clearance (Cl_T) of 83.16 l/kg/h and is not a P-glycoprotein substrate.
C o n c l u s i o n . 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.

1. Pavlovsky V.I., Tsymbalyuk O.V., Martynyuk V.S. et al. Analgesic effects of 3-substituted derivatives of 1,4-benzodiazepines and their possible mechanisms. Neurophysiol. 2013;45:427-432.

2. Aliforenko A.E., Bykov V.V., Motov V.S. et al. Analgesic activity of the bradykinin receptor antagonist – a derivative of 1,4-benzodiazepin-2-one. Cardiovascular Therapy and Prevention. 2022;21(2S):69-70. (XXIX Russian National Congress “Man and Medicine”: collection of abstracts). DOI: 10.15829/1728-8800-2022-S2. (In Russ.)

3. Aliforenko A.E., Bykov V.V., Motov V.S. et al. (2022). Addictive potential of a new analgesic – a bradykinin receptor antagonist. In Modern Medicinal Toxicology: Fundamental and Applied Aspects: proceedings of the III All-Russian Scientific Conference. Tomsk, P. 6–7. (In Russ.)

4. Kolyvanov G.B., Litvin A.A., Shevchenko R.V. et al. Pharmacokinetic relationships in psychotropic drugs effects. Farmakokinetica and Farmakodynamika. 2020;4:3-8. DOI: 10.37489/2587-7836-2020-4-3-8. (In Russ.)

5. Ivannikova E.V., Zherdev V.P., Boyko S.S. et al. Study the pharmacokinetics and bioavailability in the creation of new original drugs peptide structures and their optimum dosage forms. Pharmacokinetics and Pharmacodynamics. 2013;2:1-17. (In Russ.)

6. European Medicines Agency. Guideline on Bioanalytical Method Validation. London, 21 Jul 2011. URL: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf (accessed 10.01.2023).

7. Bioanalytical Method Validation: Guidance for Industry. 2018. URL: https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf (accessed 10.01.2023).

8. Jarc T., Novak M., Hevir N. et al. Demonstrating suitability of the Caco-2 cell model for BCS-based biowaiver according to the recent FDA and ICH harmonised guidelines. J. Pharm. Pharmacol. 2019;71(8):1231-1242. DOI: 10.1111/jphp.13111.

9. Yakusheva E.N., Chernykh I.V., Biruikova A.S. Characteristic of P-glycoprotein as a drug peptide transporter. I.P. Pavlov Russian Medical Biological Herald. 2011;19(3):142-148. DOI: 10.17816/PAVLOVJ20113142-148. (In Russ.)

10. Le Ferrec E., Chesne C., Artusson P. et al. In vitro models of the intestinal barrier. The report and recommendations of ECVAM Workshop 46. Altern. Lab. Anim. 2001;29(6):649-668. DOI: 10.1177/026119290102900604.

11. Mishra P., Pandey C.M., Singh U. et al. Selection of appropriate statistical methods for data analysis. Ann. Card. Anaesth. 2019;22(3):297-301. DOI: 10.4103/aca.ACA_248_18.

12. Sergienko V.I., Bondareva I.B. (2006). Mathematical Statistics in Clinical Research: Textbook. М.: GEOTAR-Media. 304 p. (In Russ.)

13. Chmelař V., Grossman V., Hais I.M., Demi F. Gastric retention and its changes in mice and rats during the first six days following X-irradiation. Radiat. Res. 1969;37(3):627-635. DOI: 10.2307/3572700.

14. Tshepelevitsh S., Kadam S.A., Darnell A. et al. LogP determination for highly lipophilic hydrogen-bonding anion receptor molecules. Anal. Chim. Acta. 2020;1132:123-133. DOI: 10.1016/j.aca.2020.07.024.

15. Calatayud-Pascual M.A., Sebastian-Morelló M., Balaguer-Fernández C. et al. Influence of chemical enhancers and iontophoresis on the in vitro transdermal permeation of propranolol: evaluation by dermatopharmacokinetics. Pharmaceutics. 2018.10(4):265. DOI: 10.3390/pharmaceutics10040265.

16. Djabri A., Guy R.H., Delgado-Charro M.B. Transdermal iontophoresis of ranitidine: an opportunity in paediatric drug therapy. Int. J. Pharm. 2012;435(1):27-32. DOI: 10.1016/j.ijpharm.2012.03.006.

17. Vdovin A.S., Maximchik P.V., Kulikov A.V. et al. Inhibition of P-glycoprotein stimulates cell death under hypoxia-mimicking conditions. Doklady Biochemistry and Biophysics. 2017;472:327-30. DOI: 10.1134/S1607672917010100.

18. Vengerovskii A.I. (2020). Pharmacology: Textbook. М.: GEOTAR-Media. 848 p. (In Russ.)