TOXICOKINETICS OF SULFASALAZINE (SALICYLAZOSULFAPYRIDINE) AND ITS METABOLITES IN B6C3F(1) MICE

The toxicokinetics of salicylazosulfapyridine (SASP) and its metabolit es were investigated in male and female B6C3F1 mice either following s ingle intravenous (5 mg/kg) or oral (67.5, 675, 1350, and 2700 mg/kg) doses, or following three consecutive daily oral doses (675, 1350, and 2700 mg/kg). Plasma concentrations of SASP and its metabolites were q uantified by HPLC. Upon intravenous administration, SASP rapidly disap peared from blood with a mean residence time of 0.45-0.78 hr. The only metabolite of SASP found in plasma after an intravenous dose was sulf apyridine (SP). In both sexes, the absolute oral bioavailability of SA SP ranged between 16.6-18.2% at a dose of 67.5 mg/kg, and between 2.6- 8.7% at doses of 675-2700 mg/kg. Following oral administration of SASP , both SP and AcSP were identified in plasma. The area under the plasm a concentration-time curves (AUC) of SP at all four oral doses were ap proximately 21- to 32-fold or 5- to 25-fold greater than those of SASP in male or female mice, respectively. The acetylated form of SP and A cSP, produced AUC values higher than SASP but much less than SP. Multi ple oral doses with SASP did not alter the temporal patterns of SASP a bsorption and elimination in comparison to a single dose. However, SP accumulated in both sexes following multiple oral doses. A gender-depe ndent difference in toxicokinetic profiles for SASP and SP was also ob served. Female mice displayed a higher C(max) of SASP and SP than did male mice. Although the volume of distribution of SASP was similar in both sexes, the systemic clearance of SASP in males was about twice th at observed in females. The results indicated that after SASP administ ration, the metabolites SP and AcSP displayed higher and more prolonge d plasma concentration-time profiles than parent SASP. Therefore, SP m ay accumulate in the body following repeated dosing and contribute to the genotoxicity observed following administration of high doses of SA SP.