title: Evaluation of the Intestinal Absorption Mechanism of Casearin X in Caco-2 Cells with Modified Carboxylesterase Activity.
abstract: The clerodane diterpene casearin X (1), isolated from the leaves of Casearia sylvestris, is a potential new drug candidate due to its potent in vitro cytotoxic activity. In this work, the intestinal absorption mechanism of 1 was evaluated using Caco-2 cells with and without active carboxylesterases (CES). An LC-MS method was developed and validated for the quantification of 1. The estimation of permeability coefficients was possible only under CES-inhibited conditions in which 1 is able to cross the Caco-2 cell monolayer. The mechanism is probably by active transport, with no significant efflux, but with a high retention of the compound inside the cells. The enzymatic hydrolysis assay demonstrates the susceptibility of 1 to first-pass metabolism as substrate for specific CES expressed in human intestine.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo , 14040-903 Ribeirao Preto, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Moreira da Silva
authors.affiliation: Institute for Pharma Technology, School of Life Sciences, University of Applied Sciences Northwestern Switzerland , 4132 Muttenz, Switzerland.
authors.forename: Sheela
authors.initials: S
authors.lastname: Verjee
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo , 14040-903 Ribeirao Preto, Brazil.
authors.forename: Cristiane Masetto
authors.initials: CM
authors.lastname: de Gaitani
authors.affiliation: Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirao Preto, University of Sao Paulo , 14040-901 Ribeirao Preto, Brazil.
authors.forename: Anderson Rodrigo
authors.initials: AR
authors.lastname: Moraes de Oliveira
authors.affiliation: Nucleus of Bioassays, Biosynthesis and Ecophysiology of Natural Products, Institute of Chemistry, Department of Organic Chemistry, Sao Paulo State University , 14801-970 Araraquara, Brazil.
authors.forename: Paula Carolina
authors.initials: PC
authors.lastname: Pires Bueno
authors.affiliation: Nucleus of Bioassays, Biosynthesis and Ecophysiology of Natural Products, Institute of Chemistry, Department of Organic Chemistry, Sao Paulo State University , 14801-970 Araraquara, Brazil.
authors.forename: Alberto José
authors.initials: AJ
authors.lastname: Cavalheiro
authors.affiliation: Nucleus of Research for Natural Products and Synthetics, Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo , 14040-903 Ribeirao Preto, Brazil.
authors.forename: Norberto
authors.initials: N
authors.lastname: Peporine Lopes
authors.affiliation: Institute for Pharma Technology, School of Life Sciences, University of Applied Sciences Northwestern Switzerland , 4132 Muttenz, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Butterweck
mesh_terms: D001938:Brazil; D018938:Caco-2 Cells; D043182:Carboxylesterase / Q000378:metabolism*; D037821:Casearia / Q000737:chemistry*; D045785:Diterpenes, Clerodane / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption; D015394:Molecular Structure; D018515:Plant Leaves / Q000737:chemistry
chemical_list: C548433:1-(acetyloxy)-3,5,6,6a,7,8,9,10-octahydro-10-hydroxy-7,8-dimethyl-7-(3-methylpenta-2,4-dien-1-yl)naphtho(1,8a-c)furan-3,5-diyl dibutanoate; D045785:Diterpenes, Clerodane; D043182:Carboxylesterase