Pharmacokinetics and biodistribution of topical phosphosulindac and its metabolites in mice and a mouse model for chemotherapy-induced peripheral neuropathy

Background: Our purpose was to determine the pharmacokinetics and biodistribution of phosphosulindac and its metabolites when applied to mouse skin. Phosphosulindac differs from sulindac by adding a diethyl-phospho-butane moiety, which enhances efficacy and safety. In preclinical studies, phosphosulindac has anti-cancer and anti-inflammatory properties and prevents and reverses chemotherapy-induced peripheral neuropathy Methods: Phosphosulindac gel was applied topically to the hind paws of normal mice and those with chemotherapy-induced peripheral neuropathy. Samples from the paw skin, paw muscle, leg muscle, sciatic nerve, dorsal root ganglia and blood, obtained at various time points, were assayed using HPLC for phosphosulindac, and its metabolites (sulindac, sulindac sulfide, sulindac sulfone). Results: Topically applied phosphosulindac was detected in paw skin, paw and adjacent leg muscles where it reached its Tmax in 0.5 h. Smaller amounts of phosphosulindac were detected in sciatic nerve (Tmax = 3 h) and dorsal root ganglia (at 24 h). Phosphosulindac was not found in blood. Absorption of phosphosulindac was concentration-dependent and pH-sensitive. Its metabolites were detected in paw skin, vicinal muscles, sciatic nerve, and blood but not in dorsal root ganglia. Topically applied equimolar sulindac was detected in paw skin and muscle and in smaller amounts in leg muscle and sciatic nerve. Conclusion: Phosphosulindac is absorbed through the paw skin and transported from paw and leg muscle to the sciatic nerve and dorsal root ganglia, its target tissues in normal and chemotherapy-induced peripheral neuropathy mice. In contrast, sulindac is transported through the same tissues as well as by the circulation.