The evaluation of pharmacokinetic parameters of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and its metabolites in rat plasma

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.10.523

Abstract

Introduction: 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide (ODASA) is a new pharmacologically activecompound, which is capable of reducing intraocular pressure by inhibiting carbonic anhydrase II. It is necessary to calculate the pharmacokinetic parameters of this compound and its metabolites in blood plasma of laboratory animals during a preclinical study. Aim: Evaluation of pharmacokinetic parameters of ODASA and its metabolites in rat bloodplasma after instillation of ocular suspension and its intraperitoneal administration.

Materials and Methods: The study was conducted on 2 groups of Wistar rats, each including 6 individuals. The firstgroup underwent instillation of 1% ocular suspension of ODASA of 20 µL into each eye (1.6 mg/kg). The drug was injected intraperitoneally at the same dose to the second group. Blood sampling was performed before the administration,0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72 h, 96h, 120h, 144h, 192h, 240h, 288h after the administration. Plasma was immediately stabilized by 10% solution of ascorbic acid and frozen to a temperature no higher than -70°C. The sampleswere analyzed using the HPLC-MS/MS method. Chromatographic separation was performed on a Kinetex Phenyl Hexylcolumn (50*4.6 mm, 2.6 microns) in a gradient mode. Detection was carried out in the MRM mode using electrosprayionization.

Results: The developed method was validated in the range of 2-2000 ng/mL for ODASA and 4-[5-(hydroxymethyl)-1,3,4-oxadiazole-2-yl]-benzenesulfonamide (M1) and 0.5 -500.0 ng/mL for N-hydroxy-4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide (M2). The size of the maximum plasma concentration after instillation of ODASA into eyes was 349.85±62.50 ng/mL, in M1 – 30.91±6.00 ng/mL and in M2 – 2.70±0.62 ng/mL (M±SEM). The half-life time of ODASA after ocular administration was 46.4±3.8 h, M1 – 70.0±14.3 h, and M2 - 36.5±15.2 h (M±SEM). The relative bioavailability of ODASA compared with injection was 81.03%.

Conclusion: The performed validation of the method guaranteed the accuracy of the obtained results. The activesubstance has a high relative bioavailability after instillation into eyes. M1 is a major metabolite, and M2 is a minormetabolite. The studied compounds had a long half-life.

Graphical Abstract

Keywords:

HPLC-MS/MS, plasma, stabilization, validation, pharmacokinetics, bioavailability, rats, carbonic anhydrase II inhibitor, N-hydroxysulfonamide

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Author Contribution

Alexander L. Khokhlov, Yaroslavl State Medical University

Doctor Habil. of Medical Sciences, Professor, Member of The Russian Academy of Sciences, Head of the Department of Pharmacology and Clinical Pharmacology, rector of Yaroslavl State Medical University, Yaroslavl, Russia; e-mail: al460935@yandex.ru; ORCID ID: https://orcid.org/0000-0002-0032-0341. The author’s contribution: formulation and development of the aim and objectives; analysis and   interpretation of the obtained data; critical review of the draft copy and provision of valuable comments.

Ilya I. Yaichkov, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Candidate of Pharmaceutical Sciences, research fellow of the Department of Analytical Development and Quality Control of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; research fellow of the Institute of Pharmacy of Yaroslavl State Medical University, Yaroslavl, Russia; e-mail: i.yaichkov@yspu.org; ORCID ID: https://orcid.org/0000-0002-0066-7388. The author’s contribution: concept development; development of design of pharmacokinetic study; development of bioanalytical methods; analysis of samples; analysis and interpretation of the obtained data; writing the bioanalytical part and editing the manuscript.

Anton A. Shetnev, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Candidate of Chemical Sciences, Head of the Department of Pharmaceutical Development of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical Universitynamed after K.D. Ushinsky, Yaroslavl, Russia; e-mail: a.shetnev@list.ru; ORCID ID:https://orcid.org/0000-0002-4389-461X. The author’s contribution: synthesis of substances of the drug and its metabolite.

Mikhail K. Korsakov, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Doctor Habil. of Chemical Sciences, Professor of the Department of Chemistry, Theory and Methods of Teaching Chemistry, Head of The Center of Transfer of Pharmaceutical Technology named after M.V. Dorogov of Yaroslavl State Pedagogical University named after K.D. Ushinsky, Yaroslavl, Russia; e-mail:m.korsakov@yspu.org; ORCID ID: https://orcid.org/0000-0003-0913-2571. The author’s contribution: formulation and development of the aim and objectives; analysis and interpretation of the obtained data; critical review of the draft copy and provision of valuable comments.

 

Nikita N. Volkhin , Yaroslavl State Pedagogical University named after K.D. Ushinsky

Assistant of the Department of Pharmacology and Clinical Pharmacology,; junior research fellow of the Department of Pharmacological Studies of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky, Yaroslavl, Russia; e-mail: nnvolkhin@ysmu.ru; ORCID ID: https://orcid.org/0000-0002-4275-9037. The author’s contribution: working with laboratory animals; blood and plasma sample collection.

Sergey S. Petukhov, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Engineer of the Department of Pharmacological Studies of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; junior research fellow of the Institute of Pharmacy of Yaroslavl State Medical University, Yaroslavl, Russia; e-mail: sspp465@mail.ru; ORCID ID: https://orcid.org/0009-0007-8435-7689. The author’s contribution: working with laboratory animals; blood and plasma sample collection.

Alena N. Tyushina, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Engineer of the Department of Pharmacological Studies of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; junior research fellow of the Institute of Pharmacy of Yaroslavl State Medical University, Yaroslavl, Russia; e-mail: denezhkina89@mail.ru; ORCID ID: https://orcid.org/0009-0007-8084-5239. The author’s contribution: working with laboratory animals; blood and plasma sample collection.

Olga E. Lasaryanz, Yaroslavl State Pedagogical University named after K.D. Ushinsky

Engineer of the Department of Pharmacological Studies of M.V. Dorogov Pharmaceutical Technology Transfer Center of Yaroslavl State Pedagogical University named after K.D. Ushinsky; specialist of the Institute of Pharmacy of Yaroslavl State Medical University, Yaroslavl, Russia; e-mail: lazaryants98@mail.ru; ORCID ID: https://orcid.org/0009-0002-1249-3669. The author’s contribution: working with laboratory animals; blood and plasma sample collection.

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Published

28-12-2024

How to Cite

Khokhlov AL, Yaichkov II, Shetnev AA, Korsakov MK, Volkhin NN, Petukhov SS, Tyushina AN, Lasaryanz OE (2024) The evaluation of pharmacokinetic parameters of 4-(5-methyl-1,3,4-oxadiazole-2-yl)-benzenesulfonamide and its metabolites in rat plasma. Research Results in Pharmacology 10(4): 67–76. https://doi.org/10.18413/rrpharmacology.10.523

Issue

Vol. 10 No. 4 (2024)

Section

Experimental Pharmacology

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Copyright (c) 2024 Khokhlov AL, Yaichkov II, Shetnev AA, Korsakov MK, Volkhin NN, Petukhov SS, Tyushina AN, Lasaryanz OE

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