Study on the chorology and pharmcokinetics of TIMP-1 inhibitor S-asON in rats with hepatic fibrosis

Objective To study the biologic distribution and pharmcokinetics of sulfurized thiophosphate modified antisense oligonucleotide (S asON) in rats with hepatic fibrosis, and to provide the theoretical basis for clinical application. Methods Synthesized S asON of TIMP 1, by injecting 20 S asON labelled 5′ end with γ 32p ATP into the tail vein of rats, collected urine and stool per 24h, then killed the exprimental rats at every 12 time points, took out the organs and tissues, and determined the cpm value with liquid scintillometer counter. Results S asON was found to distribute in all organs of the body, with the liver and kidney being the highest, and could be maintained for over 72h. The plasma drug elimination curve was concordant with a two compartment model. Plasma clearance rate was 0.07% /h. Urine was the major clearance way (24h, 28.4% ,72h, 44.8% , respectively). Conclusion In rats model, the liver and kidney are the major histobiologic distributed organs of S asON. Due to its longer clearance half life, it is possible to be used in the clinic practice, the result lays the groundwork for the development of a new gene therapy drug of anti hepatic fibrosis.