Stability, blood partition, and protein binding of DA-5018, a new nonnarcotic analgesic

The stability of DA-5018, a capsaicin analog as a new non-narcotic analgesic, in plasma, blood, 4% human serum albumin (HSA), and isotonic Sorensen phosphate buffer at pH 7.4 containing dextran to make 3% ('the buffer'), the blood partition of DA-5018 between plasma and blood cells, and the factors influencing the binding of DA-5018 to 4% HSA using an equilibrium dialysis technique were evaluated. DA-5018 was stable in both rat blood and plasma for up to 4 hr storage at 25° C. However, DA-5018 was unstable in both dog blood and plasma; the disappearance half-lives were 1 and 1.67 hr for dog blood and plasma, respectively, when they were kept at 25° C. DA- 5018 seemed to be stable in 'the buffer' for up to 24 hr standing at both 25° C and 37° C, and in 4% HSA at 25° C. However, DA-5018 was unstable in 4% HSA at 37° C. DA-5018 reached equilibrium very fast between blood cells and plasma in rat blood; the mean blood cells to plasma concentration ratio was 1.31 ± 0.0907. Although both blood and plasma concentrations of DA-5018 were unstable after incubation in dog blood, the blood cells to plasma concentration ratio was independent of incubation time; the mean value was 0.857 ± 0.0502. Binding of DA-5018 to 4% HSA was dependent on DA-5018 concentration, buffer pH, and incubation temperature. The binding was independent of buffers containing various chloride ion concentrations. The binding of DA-5018 was dependent on alpha-1-acid glycoprotein and HSA concentrations.