Pharmacokinetics and safety of salazosulfapyridine were studied using 18 healthy male subjects. Salazosulfapyridine (SASP), 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) degraded from SASP in large intestine, N4-acetyl-SP (Ac-SP), N4-acetyl-5'-OH-SP (AcOHSP) and N4-acetyl-5'-OH-SP-o-glucuronide (AcSP-Gluc) as SP-metabolites and acetyl-5-ASA (Ac-5-ASA) as metabolite of 5-ASA, were examined by means of HPLC. 1) Single-dose study: In the groups dosed at 500, 1, 000, and 2, 000 mg of SASP respectively, tmax was 5. 69-6. 88 hr, t1/2 was 3. 23-4. 01 hr, and excretion into urine was 3-8% ; thus, absorption of SASP through gastrointestinal tracts was considered to be low (less than 10%). Between the groups dosed at 1, 000 and 2, 000 mg respectively, an increase of dose-correlative Cmax and AUC was not noted, suggesting a possibility that absorption is saturated at the higher level of dosage. The tmax of SP delayed to 12. 45-16. 82 hr, while t1/2 was 6. 10-7. 69 hr and excretion into urine was 34. 6-71. 5% respectively. In all the groups, concentrations of Ac-SP were higher than those of SP, which showed that all the subjects in this study had very good metabolic reactions. Recovery of 5-ASA from feces was about 45%. Dosage after meals revealed delayed tmax and reduction of Cmax and AUC in both SASP and SP. 2) Multiple-dose study: Pharmacokinetic parameters of SASP on the 8th day under the multiple-dose study for 8 days revealed an increase of Cmax (8. 17 vs 11.52 μg/ml), and AUC (47.98 vs.83.36 μg/hr/ml) compared with that df the first day, but no change was noted in tmax (5.17 vs. 5.98 hr), t1/2 (2.90 vs. 3.00 hr), and kei (0.24 vs. 0.25 hr-1). Steady-state in the serum SASP concentration was reached approximately within 4 days. No accumulation of SP was noted after 8 days of administration. Concentration of total SP metabolites (Ac-SP+AcOH-SP+AcSP-Gluc) indicated values 4 to 5 times higher than that of SP, but 72 hr after the final administration nearly all of them were eliminated out of blood. No special change in clinical laboratory test was noted except two cases exceeding the normal level of GPT upon the test. As the clinical symptoms, gastrointestinal findings such as discomfort in the stomach (1 case) and lower abdominal pain (1 case) as well as mucocutaneous findings such as stomatitis (2 cases) were noted, none of which, however, were serious. From these results of pharmacokinetics, safety, and tolerance of the enteric coated tablet of salazosulfapyridine in Japanese healthy subjects, it is indicated that the next clinical trial can proceed.
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