title: Pharmacokinetic evaluation of avicularin using a model-based development approach.
abstract: The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two-compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5-mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans.
authors.affiliation: NPPNS (Núcleo de Pesquisa em Produtos Naturais e Sintéticos), Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Gabriela Amaral
authors.initials: GA
authors.lastname: Buqui
authors.affiliation: NPPNS (Núcleo de Pesquisa em Produtos Naturais e Sintéticos), Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Dayana Rubio
authors.initials: DR
authors.lastname: Gouvea
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Voelkner
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Ravi S P
authors.initials: RS
authors.lastname: Singh
authors.affiliation: NPPNS (Núcleo de Pesquisa em Produtos Naturais e Sintéticos), Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Denise Brentan
authors.initials: DB
authors.lastname: da Silva
authors.affiliation: Departamento de Farmacia, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Elza
authors.initials: E
authors.lastname: Kimura
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.affiliation: NPPNS (Núcleo de Pesquisa em Produtos Naturais e Sintéticos), Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Norberto Peporine
authors.initials: NP
authors.lastname: Lopes
authors.affiliation: Departamento de Farmacia, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Diniz
mesh_terms: D000818:Animals; D031176:Bidens / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010936:Plant Extracts / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
chemical_list: D005419:Flavonoids; D010936:Plant Extracts; C041388:avicularin