Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation.
We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-γ agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies.
Núcleo de Pesquisa em Ciências Biológicas, Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Ouro Preto, Minas Gerais, Brazil; Laboratório de Desenvolvimento Galênico e Nanotecnologia-CiPharma, Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
Giani Martins
GM
Garcia
Núcleo de Pesquisa em Ciências Biológicas, Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Ouro Preto, Minas Gerais, Brazil; Laboratório de Desenvolvimento Galênico e Nanotecnologia-CiPharma, Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
Líliam Teixeira
LT
Oliveira
Laboratório de Planejamento e Síntese de Fármacos, Universidade Federal de Pernambuco, Brazil.
Ivan da Rocha
Ida R
Pitta
Laboratório de Planejamento e Síntese de Fármacos, Universidade Federal de Pernambuco, Brazil.
Maria do Carmo Alves
Mdo C
de Lima
Centro Tecnológico CETEC SENAI-Departamento Regional de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
José Mário Carneiro
JM
Vilela
Centro Tecnológico CETEC SENAI-Departamento Regional de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Margareth Spangler
MS
Andrade
Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Brazil.
Dulcinéia Saes Parra
DS
Abdalla
Núcleo de Pesquisa em Ciências Biológicas, Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Ouro Preto, Minas Gerais, Brazil; Laboratório de Desenvolvimento Galênico e Nanotecnologia-CiPharma, Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil. Electronic address: mosqueira@ef.ufop.br.
Vanessa Carla Furtado
VC
Mosqueira
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D047495:PPAR gamma / Q000819:agonists*; D010316:Particle Size; D013154:Spleen / Q000378:metabolism; D013499:Surface Properties; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C583084:5-((5-bromo-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)thiazolidine-2,4-dione; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D053769:Nanocapsules; D047495:PPAR gamma; D045162:Thiazolidinediones
Bioanalytical method; Biodistribution; LYSO-7 or [(5Z)-5-[5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione] (CAS Registry Number 1505484-42-3); Nanocapsules; Peroxisome proliferator-activated receptor-γ agonist; Pharmacokinetics; Poloxamer 188 or Polyoxyethylene-polyoxypropylene Block Copolymer (PubChem CID: 10129990); Poly(d,l-lactide) (PubChem CID: 24877805); Thiazolidinedione