Pre-clinical pharmacokinetics and acute toxicological evaluation of a monastrol derivative anticancer candidate LaSOM 65 in rats.
1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats. 2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1 mg/kg) and oral (p.o., 10 and 30 mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5 mg/kg) and p.o. (50, 100 and 150 mg/kg) administration. 3. Short half-life (1.75 ± 0.71 h), a clearance of 0.85 ± 0.18 L/h/kg and a volume of distribution of 1.76 ± 0.24 L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3 h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects. 4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate.
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre , RS , Brazil .
Bruna G S
BG
Torres
Flávia De Toni
Fde T
Uchôa
Maiara C
MC
Pigatto
Francine J
FJ
Azeredo
Sandra E
SE
Haas
Eliane
E
Dallegrave
Rômulo F S
RF
Canto
Vera L
VL
Eifler-Lima
Teresa
T
Dalla Costa
D000273:Adipose Tissue / Q000378:metabolism; D061605:Administration, Intravenous; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D008168:Lung / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013871:Thiones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute
C584768:5-ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2-(1H)-thione; D000970:Antineoplastic Agents; D011743:Pyrimidines; D013871:Thiones; C400223:monastrol