Research output: Contribution to journal › Article › peer-review
Pharmacokinetics and Dose Proportionality Study of a Novel Antiparkinsonian Agent, a 1H-1,2,4-Triazol-3-ylthio-conjugate of Prottremine. / Gorina, Daria S.; Lastovka, Anastasiya V.; Rogachev, Artem D. et al.
In: Molecules, Vol. 29, No. 18, 4498, 09.2024.Research output: Contribution to journal › Article › peer-review
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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 -
ID: 60797162