Kinetic disposition, in vitro metabolism and intestinal permeability of the govaniadine alkaloid

Author(s)

Lucas Maciel Mauriz Marques

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2017-02-20

Examining board members

Norberto Peporine Lopes; Vanderlan da Silva Bolzani; Teresa Cristina Tavares Dalla Costa; Maria Jose Vieira Fonseca; Ricardo Vessecchi Lourenço

• Advisor: Norberto Peporine Lopes

Abstract

Throughout humankind history, natural products from plants have been investigated and have been used in the treatment of countless diseases. Tetrahydroprotoberberine alkaloids from the Corydalis, in particular govaniadine, has been identified as a new category of dopaminergic ligands and responsible for analgesic, antimalarial, leishmanicidal and antiurease properties. Taking these data into account, the aim of this work was to investigate the pharmacokinetic profile, the in vitro metabolism and the intestinal permeability of the alkaloid govaniadine. As a general result for the in vitro metabolism, employing animal and human microsomal fraction, five metabolites were obtained: one O-demethylated (M1); one dihydroxylated (M2); one monohydroxylated (M3) and two glucuronidated (M4 and M5). A LC-MS/MS method was developed and validated for the investigation of the govaniadine pharmacokinetic profile in rat plasma following intravenous administration. The mean plasma concentration versus time profile was best fitted to a two-compartmental model, with a distribution half-life = 9.2 ± 8.9 min, clearance = 41.7 ± 30, 4 mL min-1 kg-1 and an elimination half-life = 55.1 ± 37.9 min. Regarding cell viability studies, govaniadine showed moderate cytotoxic effects against Hep G2, HeK-T-293 and CCF-STTG1 cell lines at concentrations up to 100 ?mol L-1. In vitro intestinal permeability study in Caco-2 model, suggests passive diffusion transport, with an apparent permeability value of 20.6 ± 3.9 × 10-6 cm/s and an efflux rate of 0.55 . These results will be important to guide future experiments concerning govaniadine pharmaceutical development (AU)

• FAPESP's process: 13/16496-5 - In vitro, in vivo metabolism and pharmacokinetic profile evaluation of the alkaloid govaniadine
• Grantee: Lucas Maciel Mauriz Marques
• Support Opportunities: Scholarships in Brazil - Doctorate