Toxicokinetics of sulfasalazine (salicylazosulfapyridine) and its metabolites in B6C3F₁ mice

The toxicokinetics of salicylazosulfapyridine (SASP) and its metabolites were investigated in male and female B6C3F₁ mice either following single 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 quantified by HPLC. Upon intravenous administration, SASP rapidly disappeared 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 sulfapyridine (SP). In both sexes, the absolute oral bioavailability of SASP 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 plasma concentration-time curves (AUC) of SP at all four oral doses were ~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 AcSP, produced AUC values higher than SASP but much less than SP. Multiple oral doses with SASP did not alter the temporal patterns of SASP absorption and elimination in comparison to a single dose. However, SP accumulated in both sexes following multiple oral doses. A gender-dependent difference in toxicokinetic profiles for SASP and SP was also observed. 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 that observed in females. The results indicated that after SASP administration, the metabolites SP and AcSP displayed higher and more prolonged plasma concentration-time profiles than parent SASP. Therefore, SP may accumulate in the body following repeated dosing and contribute to the genotoxicity observed following administration of high doses of SASP.