Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: an anti-inflammatory candidate.
OBJECTIVE
Novel 5-benzilidene thiazolidinones have been synthesized and exhibited anti-inflammatory activity. In this work one of the compounds of the thiazolidinone chemical series, (5Z,E)-3-[2-(4-chlorophenyl)-2-oxoethyl]-5-(1H-indol-3-ylmethylene)-thiazolidine-2,4-dione (PG15) was investigated aiming to determine the drug's anti-inflammatory potential in pre-clinical studies.


METHODS
Methods used included the in-vitro inhibition of cyclooxygenase-1 and -2, in-vivo evaluation of anti-inflammatory activity by air pouch and peritonitis models and the pharmacokinetic profile after intravenous (3 mg/kg) and oral (3 and 6 mg/kg) dosing to rats.


RESULTS
A two-compartment model with a fast distribution and an elimination half-life of 5.9 +/- 3.8 h described the PG15 plasma profile after intravenous dosing. PG15 showed an erratic and rapid absorption following oral administration with peak concentrations between 0.5 and 1 h. PG15 0.1 microM inhibited more than 30% and 13% of purified cyclooxygenase-1 and -2 activity in vitro, respectively. A lack of dose dependency was observed for the anti-inflammatory effect in the dose range investigated (0.8-50 mg/kg), with a maximum of 67.2 +/- 4.6% inhibition of leucocyte migration in the carrageenan-induced air pouch model obtained with the 3 mg/kg dose, similar to that observed for indometacin 10 mg/kg.


CONCLUSIONS
The erratic absorption of PG15 observed after oral dosing could explain the lack of anti-inflammatory dose dependency.
Uchôa
Flávia De Toni
Fde T
Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal do Rio Grande do Sul, Brazil.
da Silva
Teresinha Gonçalves
TG
de Lima
Maria do Carmo Alves
Mdo C
Galdino
Suely Lins
SL
Pitta
Ivan da Rocha
Ida R
Dalla Costa
Teresa
T
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D007275:Injections, Intravenous; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010538:Peritonitis / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D053778:Thiazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
C539665:(5Z,E)-3-(2-(4-chlorophenyl)-2-oxoethyl)-5-(1H-indol-3-ylmethylene)-thiazolidine-2,4-dione; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D053778:Thiazolidines; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D007213:Indomethacin