Studies On Toxicity And Toxicokinetics Of UTD1, A New Anti-Cancer Drug

UTD1 is a class I new anti-tumor drug, an antimitotic agent with the same mechanism as paclitaxel. Compared with paclitaxel, UTD1 has higher water-solubility, higher anti-tumor activity. Beagle dogs were given intravenous doses of UTD1 for 3 months with a 28 days recovery period. The dose levels were 20, 40 and 60 mg/m² (1, 2 and 3 mg/kg), respectively. The toxicity, exposure profile and its effects on cytochrome P450 isoforms in humans and dogs in vitro and ex vivo were investigated.We conducted a study in Beagle dogs exposed to UTD1 at doses of 0, 20, 40 and 60 mg/m² for 3 months intravenously and a 28 days recovery. Clinical signs, hematology, clinical chemistry and pathology were examined. The results showed main toxicity of UTD1 was targeted on digestive system, especially in lower digestive tract and inhibition of hematopoietic system. The injuries were recovered after a 28 days recovery period. Besides, UTD1 may cause atrophy of testes in male dogs.Serum samples, prepared from Beagle dogs after first dosing and last dosing of UTD1, were analysed using LC-MS. C_max, AUC and MRT kinetics parameters were determined. No statistic significant difference were observed between all the parameters after first dosing compared with those after last dosing.Dog liver microsomes were prepared from Beagle dogs after intravenous doses of 0, 20,40 and 60 mg/m² for 3 months and from the dogs after 28 days recovery period. The dog microsomes were incubated with selective substrates in presence of β-NADPH, the cofactor of CYP450s, for 30 minutes. The formations of metabolites were measured using HPLC. Dose-dependent inhibition of CYP1A2 and 3A4 were observed. Such inhibitions of CYP1A2 and 3A4 were recovered after 28 days recovery period at doses of 20 and 40 mg/m². In vitro results of human liver microsomal incubation suggests the mechanism was mixed competitive and non-competitive inhibition.