The enzyme-inducing effect of the original anticonvulsant Galodif is a modulating time factor, prospects for clinical use in the treatment of paroxysmal disorders

The enzyme-inducing effect of the original anticonvulsant Galodif is a modulating time factor, prospects for clinical use in the treatment of paroxysmal disorders

 

Authors

 

T.V. Shushpanova

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation

T.P. Novozheeva

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation; Federal State Budgetary Educational Institution of Higher Education “Siberian State Medical University”, Tomsk, Russian Federation

O.A. Vasilieva

Federal State Budgetary Educational Institution of Higher Education “Siberian State Medical University”, Tomsk, Russian Federation

V.V. Udut

Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation

 

https://doi.org/10.26617/1810-3111-2023-4(121)-61-69

 

Journal:Siberian Herald of Psychiatry and Addiction Psychiatry. 2023; 4 (121): 61-69.

 

Abstract

Introduction. Improving pharmacotherapy is possible through the creation of new drugs and optimization of therapeutic monitoring. This approach can be implemented provided that the characteristics of the biotransformation of the drug by enzymes of the liver monooxygenase system (MOS), its pharmacokinetics and pharmacodynamics in the body are studied. Objective: to study the parameters of the pharmacokinetics of Galodif, to evaluate the enzyme-inducing effect on the microsomal cytochrome P450-dependent oxidation system of the liver of experimental white rats, depending on the duration of administration. Material and Methods. The experiments were carried out on 50 white outbred male rats weighing 200-220 grams. Galodif was administered in the form of a suspension of 1% starch mucus intragastrically at a dose of 100 mg/kg for a period of 1, 5 and 15 days. The animals were decapitated, and the liver was perfused with an ice-cold solution of potassium chloride. The microsomal fraction from rat liver homogenate was obtained by high-speed centrifugation. Protein content was determined using the Lowry micromethod. The content of cytochrome CYP450 in the microsomal fraction was assessed using the method of Omura and Sato. The spectra were recorded on a Hitachi-557 differential spectrophotometer (scanning dual-beam mode). Galodif was extracted by centrifugation from rat liver homogenate with chloroform at neutral pH. The measurement was carried out using a spectrophotometer at a wavelength of 433 nm. The concentration of Galodif was calculated from the calibration graph. Pharmacokinetic parameters were calculated using the model-independent method of statistical moments. The statistical significance of differences was assessed using the Kolmogorov-Smirnov λ test at p<0.05 using STATISTICA for Windows v. 12.0. Results. A single administration of Galodif to rats was accompanied by a slowdown in its elimination from the body: the values of T½, MRT, MET, AUC increased, and the clearance of the drug decreased, that indicated the retention of Galodif in the tissues of the body. A 5-fold administration stimulated the elimination of the drug from the body: T½ and AUC values decreased, MRT and MET values increased. Pharmacokinetic parameters correlated with indicators of the functional state of the liver MOS; a pronounced induction of cytochrome P450 was observed. The parameters of drug elimination from the liver indicated a pronounced tissue availability of Galodif molecules. With a 15-fold administration, the elimination of the drug slowed down, remaining accelerated relative to a single administration. Pharmacokinetic parameters of drug elimination from the liver indicated a pronounced acceleration of the passage of Galodif molecules through the hepatobiliary tract. Conclusion. The dynamics of the pharmacokinetic parameters of Galodif in the liver of experimental rats correlated with the enzyme-inducing effect on the liver MOS, depending on the duration of administration. A pronounced induction of cytochrome P450 was observed. Elimination parameters from the liver indicated a pronounced tissue availability of Galodif molecules. With a 15-fold administration, the elimination of Galodif from the body slowed down compared to a 5-fold administration, but remained accelerated compared to a single administration. Pharmacokinetic parameters of the elimination of Galodif from the liver indicated a pronounced acceleration of the passage of its molecules through the hepatobiliary tract, which is significant in the case of long-term administration for paroxysmal disorders, alcohol dependence, to prevent the development of relapse and alcoholic delirium.

 

Keywords: anticonvulsant, Galodif, paroxysm, liver, cytochrome P450, microsomal oxidation system, pharmacokinetic.

 

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Materials

 

For citation: Shushpanova T.V., Novozheeva T.P., Vasilieva O.A., Udut V.V. The enzyme-inducing effect of the original anticonvulsant Galodif is a modulating time factor, prospects for clinical use in the treatment of paroxysmal disorders. Siberian Herald of Psychiatry and Addiction Psychiatry. 2023; 4 (121): 61-69. https://doi.org/10.26617/1810-3111-2023-4(121)-61-69

 

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