TY - JOUR

T1 - Pharmacokinetics and Dose Proportionality Study of a Novel Antiparkinsonian Agent, a 1H-1,2,4-Triazol-3-ylthio-conjugate of Prottremine

AU - Gorina, Daria S.

AU - Lastovka, Anastasiya V.

AU - Rogachev, Artem D.

AU - Podturkina, Alexandra V.

AU - Pavlova, Alla V.

AU - Ardashov, Oleg V.

AU - Li-Zhulanov, Nikolai S.

AU - Tolstikova, Tatyana G.

AU - Volcho, Konstantin P.

AU - Salakhutdinov, Nariman F.

PY - 2024/9

Y1 - 2024/9

N2 - 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.

AB - 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.

KW - LC–MS/MS

KW - Parkinson’s disease

KW - bioavailability

KW - dose proportionality

KW - monoterpene

KW - pharmacokinetic

KW - validation

UR - https://www.mendeley.com/catalogue/2bff1919-a678-3f56-9577-4b1a0b273cfe/

U2 - 10.3390/molecules29184498

DO - 10.3390/molecules29184498

M3 - Article

C2 - 39339493

VL - 29

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 18

M1 - 4498

ER -