Pharmacokinetics and Dose Proportionality Study of a Novel Antiparkinsonian Agent, a 1<i>H</i>-1,2,4-Triazol-3-ylthio-conjugate of Prottremine
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 dop...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-09-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/29/18/4498 |
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| Summary: | 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 (<i>p.o.</i>) and intravenous injection (<i>i.v.</i>) at various doses. The dose proportionality was also evaluated after a single <i>p.o.</i> administration of three ascending doses (1, 5, and 10 mg/kg) and a single <i>i.v.</i> 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. |
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| ISSN: | 1420-3049 |