Effect of pharmacotherapy on the pharmacokinetic parameters of the model substrate antipyrine ‒ a test evidence of the processes of xenobiotic elimination in saliva in patients with mental disorders

Effect of pharmacotherapy on the pharmacokinetic parameters of the model substrate antipyrine ‒ a test evidence of the processes of xenobiotic elimination in saliva in patients with mental disorders

 

Authors

 

T.V. Shushpanova

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation; Tomsk Research Institute of Balneology and Physiotherapy ‒ branch of “Federal Scientific and Clinical Center of Medical Rehabilitation and Balneology of the Federal Medical and Biological Agency”, Tomsk, Russian Federation

I.E. Kupriyanova

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

A.I. Mandel

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

T.V. Kazennykh

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

T.P. Novozheeva

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

E.D. Schastnyy

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

O.E. Perchatkina

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

N.I. Kisel

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

I.I. Ukraintsev

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

I.N. Smirnova

Tomsk Research Institute of Balneology and Physiotherapy ‒ branch of “Federal Scientific and Clinical Center of Medical Rehabilitation and Balneology of the Federal Medical and Biological Agency”, Tomsk, Russian Federation

A.A. Zaitsev

Tomsk Research Institute of Balneology and Physiotherapy ‒ branch of “Federal Scientific and Clinical Center of Medical Rehabilitation and Balneology of the Federal Medical and Biological Agency”, Tomsk, Russian Federation

G.Yu. Selivanov

Federal State Budgetary Educational Institution of Higher Education “St. Petersburg University of the State Fire Service of the Ministry of Emergency Situations of Russia”, Saint Petersburg, Russian Federation

O.A. Vasilieva

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

 

https://doi.org/10.26617/1810-3111-2024-4(125)-66-81

 

Journal: Siberian Herald of Psychiatry and Addiction Psychiatry. 2024; 4 (125):  66-81.

 

Abstract

Introduction. Medicines (M), including psychotropic drugs, can change the activity of microsomal enzymes of the cytochrome P450-dependent microsomal oxidation system (MOS) of xenobiotics in a patient and lead to a change in the drug level due to drug interference associated with the induction of key MOS enzymes, and to a decrease in the effectiveness of the therapy. The action of psychotropic drugs can largely depend on the rate of their elimination from the body. Objective: to evaluate the effect of psychopharmacotherapy of conventionally used psychotropic drugs and the original anticonvulsant halodif (meta-chlorobenzhydryl urea) on the rate of metabolism of the model substrate antipyrine (AP) in saliva from patients with mental disorders. Materials and Methods. The study was conducted in the Borderline and Addictive States Departments of Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences. The study sample included male patients with nonpsychotic mental disorders (n=34) and alcohol dependence (n=36), mean age was 42.73±4.39 years. In accordance with the diagnosis according to ICD-10, patients with nonpsychotic mental disorders were divided into 3 groups: group 1 ‒ adjustment disorder with predominant disturbance of other emotions (F43.23) and adjustment disorder with mixed disturbance of emotions and conduct (F43.25), group 2 ‒ organic emotionally labile (asthenic) disorder due to cerebrovascular disease (F06.61), group 3 ‒ mixed anxiety and depressive disorder (F41.2). Patients with alcohol dependence were diagnosed with alcohol dependence syndrome, currently abstinence during treatment (F10.232) and uncomplicated alcohol withdrawal syndrome (F10.302). The drugs with anxiolytic and normotonic action were administered to patients with nonpsychotic mental disorders: group 1 ‒ alprazolam, group 2 ‒ bromazepam, group 3 ‒ lithium carbonate; the course of therapy was 21 days. The comparison group included 20 healthy volunteers. The influence of the enzyme-inducing action of the anticonvulsant halodif on the PK parameters of AP was assessed in saliva in healthy volunteers and in patients. Determination of the PK parameters of AP as test evidence of the processes of elimination from the body of patients and volunteers was carried out before the administration of the drugs and at the end of therapy at a dose of 10 mg / kg once on an empty stomach. Saliva samples were collected 0.5; 1.0; 2.0; 3.0; 6.0; 12.0; 24.0 hours after antipyrine administration. Antipyrine concentration was determined spectrophotometrically. Pharmacokinetic parameters: half-life (T1/2, h), total clearance (CLt, ml/min), area under the pharmacokinetic curve (“concentration-time”) (AUC, μg min/ml) were estimated using the Piotrowski method (1986). Statistical data processing was performed using the Statistika 12.0 software package for Windows, nonparametric Kolmogorov-Smirnov l-goodness-of-fit test. Results. Administration of alprazolam to patients of the 1st group at a dose of 0.5-1.5 mg/day for 21 days did not have a significant effect on the PK parameters of AP: T1/2, CLt, AUC, characterizing the functional state of oxidative metabolism in the patients' bodies. Comparison of the PK parameters of antipyrine during administration of bromazepam at daily doses of 6-12 mg with background values in patients of the 2nd group did not reveal statistically significant differences, which indicated accelerated elimination of antipyrine due to the concomitant therapy. A background decrease in T1/2, an increase in CLt, a decrease in the concentration-time curve due to the vascular, nootropic and vitamin therapy were found. In patients of the 3rd group, lithium carbonate therapy at a dose of 500-1000 mg did not change the PK parameters of antipyrine elimination. The results of the study indicate that the studied psychotropic drugs in the specified doses have no effect on the activity of the liver MOS in patients of all 3 groups. While the administration of halodif caused the induction of MOS and changed the PK parameters of antipyrine: in healthy volunteers ‒ a 2-fold decrease in T1/2, in patients with alcohol dependence ‒ a significant 5-fold decrease in T1/2, an increase in CLt, a decrease in AUC, which indicates accelerated elimination of antipyrine from the saliva of the subjects. Conclusion. Psychopharmacotherapy with the administration of alprazolam, bromazepam, lithium carbonate in the specified therapeutic doses did not cause a significant effect on the PK of antipyrine, a test evidence of xenobiotic elimination processes in patients with mental disorders, and indicates the absence of drug pharmacokinetic interference. Halodif had a stimulating effect on the induction of liver MOS in patients and volunteers, significantly changing the PK parameters of antipyrine elimination.

 

Keywords: mental disorders, alcohol, alprazolam, bromazepam, lithium carbonate, halodif, biotransformation, pharmacokinetics, antipyrine, liver, xenobiotic, cytochrome P450, microsomal system.

 

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Materials  

For citation: Shushpanova T.V., Kupriyanova I.E., Mandel A.I., Kazennykh T.V., Novozheeva T.P., Schastnyy E.D., Perchatkina O.E., Kisel N.I., Ukraintsev I.I., Smirnova I.N., Zaitsev A.A., Selivanov G.Yu., Vasilieva O.A. Effect of pharmacotherapy on the pharmacokinetic parameters of the model substrate antipyrine ‒ a test evidence of the processes of xenobiotic elimination in saliva in patients with mental disorders. Siberian Herald of Psychiatry and Addiction Psychiatry.2024; 4 (125): 66-81. https://doi.org/10.26617/1810-3111-2024-4(125)-66-81

 

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