Pharmacokinetics and Dose Proportionality Study of a Novel Antiparkinsonian Agent, a 1H-1,2,4-Triazol-3-ylthio-conjugate of Prottremine

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 18; p. 4498
• Main Authors: Gorina, Daria S., Lastovka, Anastasiya V., Rogachev, Artem D., Podturkina, Alexandra V., Pavlova, Alla V., Ardashov, Oleg V., Li-Zhulanov, Nikolai S., Tolstikova, Tatyana G., Volcho, Konstantin P., Salakhutdinov, Nariman F.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.09.2024; MDPI
• Subjects: Acids; Antiparkinsonian agents; Bioavailability; Brain research; Chromatography; Clinical trials; Disease; Dopamine; dose proportionality; Drug dosages; LC–MS/MS; Metabolism; Nervous system diseases; Parkinson’s disease; pharmacokinetic; Pharmacokinetics; Solvents; Toxicity; validation; Germany; Russia
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29184498

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.