Pharmacokinetics of Salazosulfapyridine (Sulfasalazine, SASP)(III)Metabolism and biliary excretion of SASP in the rat after a single intravenous or oral administration.

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The metabolites formed from [³H, ¹⁴C]salazosulfapyridine (sulfasalazine, SASP), were investigated in urine, faeces, bile and ten different organs from rats after a single oral or intravenous dose. The metabolites were fractionated by liquid chromatography and conclusively identified by mass spectrometry. The metabolites identified in urine were 5-aminosalicylic acid(5ASA), 5-acetamidosalicylic acid(Ac5ASA), sulfapyridine(SP) and 5-hydroxy-sulfapyridine (SPOH) together with glucuronide, sulphate and/or acetyl conjugates of SPOH. The female rats formed no or very small amounts of hydroxylated and conjugated metabolites compared to male rats.
The collected organs and their major metabolite content were as follows : stomach(SASP), duodenum (SASP and SP), ileum (SASP and SP), caecum(SP, SPOH and AcSPOH), colon (SP), lung (SP and SASP), liver (SP, AcSP and SASP), kidney (SP, AcSP and SASP), thyroid (SASP) and testis (SP and AcSP).
The metabolites found in bile after an oral dose were SP, AcSP and glucuronide and sulphate conjugates of these as well as Ac5ASA and unchanged SASP. The bile from male rats contained higher concentrations of conjugated metabolites than bile from female rats. Only intact SASP was found after the i.v. dose.
The cumulative excretion of [¹⁴C, ³H]SASP was studied in bile collected during 24 hours after p.o. or i.v. administration. The recovery of total radioactivity in bile from female rats after i.v. administration was 101.6±1.8%(mean±SEM)and 103.5±1.4% of administered dose for ¹⁴C and ³H respectively. The corresponding figures for male rats were 88.0±4.1% for ¹⁴C and 88.1±4.2% for ³H. The excretion of SASP in bile after i.v. administration was 99.8 % of the administered dose in female rats and 85.9% in the male rats. After an oral dose the biliary excretion of ¹⁴C radioactivity representing SASP and5ASA metabolites was low, 3.86±0.79% for females and 5.71±0.95% for male rats. The ^3H excretion including SASP but consisting most of SP metabolites was significantly higher in the male rats, 38.3±3.7% compared to 10.5±2.1% in female rats. The reason for this sex differences was the formation of hydroxylated SP and further conjugation in male rats. The biliary excretion of SASP after oral administration was similar in both sexes 2.74±0.37% for female rats and 2.52±0.45% for male rats. Since the biliary excretion of the unchanged drug was < 3 % after p.o. administration enterohepatic cycling was not studied.
In conclusion, SASP underwent azoreduction to form 5ASA and SP. Both these metabolites were acetylated. SP was also hydroxylated particularly in the male rats. The SPOH was conjugated both with sulfate and glucuronic acid.