Preclinical pharmacokinetic studies of villocarine A, an active Uncaria alkaloid.

Autor: Chiang YH; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Chear NJ; Centre for Drug Research, Universiti Sains Malaysia, Gelugor, Penang, Malaysia., Berthold EC; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Kuntz MA; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Kanumuri SRR; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, Florida, USA., Senetra AS; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Ramanathan S; Centre for Drug Research, Universiti Sains Malaysia, Gelugor, Penang, Malaysia., McCurdy CR; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, Florida, USA.; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Sharma A; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, Florida, USA.
Jazyk: angličtina
Zdroj: Drug testing and analysis [Drug Test Anal] 2024 May 15. Date of Electronic Publication: 2024 May 15.
DOI: 10.1002/dta.3703
Abstrakt: Villocarine A is a bioactive indole alkaloid isolated from the Uncaria genus. It has demonstrated vasorelaxation activity and potential to protect the central nervous system. To identify the pharmacokinetic properties of villocarine A, a series of in vitro and in vivo studies have been performed. Villocarine A was found to be highly permeable (15.6 ± 1.6*10 -6  cm/s) across human colorectal adenocarcinoma cell monolayer with high protein binding (>91%) in both rat and human plasma. Hepatic extraction ratio of villocarine A was 0.1 in pooled rat liver and 0.2 in human liver microsomes and was found stable in rat plasma at 37°C. Due to the high permeability and low rate of metabolism properties, villocarine A was initially considered suitable for preclinical development and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification (linearity: 1-150 ng/ml) in rat plasma was developed and validated for in vivo studies. Essential pharmacokinetic parameters included the volume of distribution and clearance of villocarine A, which were found to be 100.3 ± 15.6 L/kg and 8.2 ± 1.1 L/h/kg, respectively, after intravenous administration in rats. Following oral dosing, villocarine A exhibited rapid absorption as the maximum plasma concentration (53.2 ± 10.4 ng/ml) occurred at 0.3 ± 0.1 h, post-dose. The absolute oral bioavailability of villocarine A was 16.8 ± 0.1%. To our knowledge, this was the first pharmacokinetic study of villocarine A, which demonstrated the essential pharmacokinetic properties of villocarine A: large volume distribution, high clearance, and low oral bioavailability in rats.
(© 2024 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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