Abstract: SA-PO649

Targeting Stat3 Activity Blocks Muscle Wasting in CKD

Session Information

Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

  • 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Authors

  • Zhang, Liping, Nephrology, Baylor College of Medicine, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
Background

Muscle wasting with morbidity and mortality is common in patients with chronic kidney disease (CKD) but there are no regularly effective treatments. We find there is activation of a p-Stat3/CEBPδ/myostatin signaling pathway in muscles of patients or mice with CKD and inhibition of myostatin or p-Stat3 blocked muscle loss in mice with CKD. We also find that C188-9, a small-molecule inhibitor of Stat3 increases muscle mass and improves muscle function despite CKD. To extend these results, we examined optimal dosing, frequency and route of administration of C188-9 to rats with CKD

Methods

CKD (subtotal nephrectomy) was created in male Sprague-Dawley rats. C188-9 was administered by gavage feeding or i.p. injection; plasma levels of C188-9 were measured by LC/MS

Results

For pharmacokinetics, we administered C188-9 (doses 0, 10, 30, 100 mg/kg) once to 2 groups of rats: A) sham-operated, control rats; and B) rats with CKD, pair fed with control rats. Plasma was collected at 0, 0.25, 0.5 1, 2, 4, 8 and 24 hr following C188-9 treatment. We found: 1) plasma C188-9 concentrations were linear with the administered dose in control and CKD rats. 2) C188-9 plasma concentrations in mg/ml were similar in CKD vs. control rats at different doses: 10 (CKD, 2.5 vs control, 2.4); 30 (8.4 vs. 8.3) and 100 mg/kg, (13 vs. 9.8). 3). Time to maximal C188-9 blood level was 1h for all doses of control and CKD rats. 4) In CKD rats, the C188-9 half-life was greater vs. results in control rats. 5) At 3 days after C188-9 dosing, we measured C188-9 in muscle lysates; levels of C188-9 in muscle were similar in sham and CKD rats. 6) Notably, C188-9 suppressed muscle p-Stat3 levels in CKD rats vs. controls (no C188-9) and the p-Stat3 level was inversely correlated with the C188-9 in muscle. 7). C188-9 was tolerated in CKD rats even at 100 mg C188-9/kg/day for 7 days

Conclusion

1) the optimal C188-9 dose is 30mg/kg which blocks p-Stat3 effectively in muscle of rats with CKD and it has a half-life similar to that of 100 mg/kg. 2) From this half-life, C188-9 could be dosed every 4 hrs to CKD rats. 3) C188-9 has a potential for developing oral dosing as results with gavage feeding were similar to those of i.p. injection. 4) The drug remains in muscles, inhibiting p-Stat3 effectively. 5) C188-9 exhibits minimal short-term toxicity. Thus, C188-9 has a potential for combating muscle wasting in patients with CKD.

Funding

  • NIDDK Support