1. Pharmacokinetics and Dose Proportionality Study of a Novel Antiparkinsonian Agent, a 1 H -1,2,4-Triazol-3-ylthio-conjugate of Prottremine.
- Author
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Gorina DS, Lastovka AV, Rogachev AD, Podturkina AV, Pavlova AV, Ardashov OV, Li-Zhulanov NS, Tolstikova TG, Volcho KP, and Salakhutdinov NF
- Subjects
- Animals, Mice, Male, Triazoles pharmacokinetics, Triazoles administration & dosage, Tandem Mass Spectrometry, Dose-Response Relationship, Drug, Biological Availability, Parkinson Disease drug therapy, Parkinson Disease metabolism, Administration, Oral, Chromatography, High Pressure Liquid, Mice, Inbred C57BL, Disease Models, Animal, Antiparkinson Agents pharmacokinetics, Antiparkinson Agents administration & dosage, Antiparkinson Agents chemistry
- Abstract
The novel antiparkinsonian agent PA-96 is the focus of our research. PA-96 supported the survival of cultured naïve dopamine neurons, alleviated motor deficits in MPTP and haloperidol-based mice models of Parkinson's disease, and increased the density of tyrosine hydroxylase positive neurons and dopamine concentration in the midbrain of an MPTP-damaged brain. In this work, an HPLC-MS/MS method was developed and validated, and the pharmacokinetics of the agent was investigated in mice after a single or multiple oral administration ( p.o. ) and intravenous injection ( i.v. ) at various doses. The dose proportionality was also evaluated after a single p.o. administration of three ascending doses (1, 5, and 10 mg/kg) and a single i.v. injection of two doses (1 and 10 mg/kg); also, the bioavailability was estimated. The disproportionality of pharmacokinetic parameters could be explained by the saturation of active centres of enzymes or receptors binding the substance: at low doses, part of the compound is bound, leaving a small amount circulating in blood, and rapidly metabolised and/or bound too. The bioavailability of PA-96 was c.a. 7 and 35% for the doses of 5 and 10 mg/kg, correspondingly.
- Published
- 2024
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