Pharmacokinetics (PK) and pharmacodynamics (PD) of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease.

Pharmacokinetics (PK) and pharmacodynamics (PD) of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease. Am J Physiol Renal Physiol. 2020 Jun 01;: Authors: Zhang L, Wang Y, Dong Y, Chen Z, Eckols TK, Kasembeli MM, Tweardy DJ, Mitch WE Abstract Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD) and there are no reliable preventive treatments. We uncovered a STAT3, CEBPδ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment of CKD-induced cachexia, we measured TTI-101 pharmacokinetics (PK) and pharmacodynamics (PD) in control and CKD rats that were orally administrated TTI-101or its diluent. Two groups of gavage-fed rats, sham-operated, control rats and CKD rats were studied. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8 and 24 hr.) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS and PK results analyzed with the PKsolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations (Cmax) and time to maximal (Tmax) plasma levels (~1 hour) were similar in sham-operated, control and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced ...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research