Pharmacokinetics of Salazosulfapyridine (Sulfasalazine, SASP)(IV):Pharmacokinetics of SASP in the rat following consecutive oral doses.

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Repeated daily oral doses of [¹⁴C, ³H]salazosulfapyridine 50mg/kg b.w. was given to male and female rats during 21 days to investigate the absorption, tissue distribution and elimina tion of SASP and metabolites. The peak plasma level of radioactivity was slightly increased for both ³H and ¹⁴C during repeated administration although the increase was not statistically significant. The elimination rate from plasma was similar after the last 21st dose as after a single dose. Thus the 24 hour plasma level was not increased. The concentration of unchanged SASP in plasma was too low to be measurable by liquid chromatography. There was no significant binding of radioactivity to the erythrocytes after the first dose, but after repeated doses some distribution of ¹⁴C to the blood cells was seen.
The dominating picture of the tissue distribution was that most of the radioactivity remained in the gastrointestinal tract. Even 96 hours after the last dose, when only trace amounts of radioactivity remained, the highest radioactivity was found in caecum.
Except for the gastrointestinal tract, the concentration of radioactivity was initially lower in the tissues than in plasma and was dominated by ³H. The concentration of ³H in tissues in relation to the plasma concentration was not changed during the repeated administration. However, the ¹⁴C concentration increased.
The tissue distribution was also studied by autoradiography and image analysis after the same pretreatment as above and with a final high dose of [³H]SASP. The time points studied were 4, 16, and 96 hours after the last given dose. The highest uptake was noticed in the connective tissues, the lung, the kidney, the epididymis, the penis and the pituitary gland.
With whole body autoradiography the tissue distribution was also studied 5 min, 1 hour and 16 hours after an i.v. injection of ¹⁴C-or ³H-labelled SASP in pregnant rats, which had been pretreated orally in 10 days with unlabelled SASP. The aim of this study was to inves tigate whether such a pretreatment caused an altered distribution pattern, compared to that after an i.v. single dose, in the fetal and placental tissues. The fetal concentration did not rise significantly. However, the maternal tissues indicated a slight increase for most tissues.
No changes were found in the excretion of radioactivity or in the metabolite pattern in urine and faeces during the administration. Neither did a consecutive administration of SASP cause any induction of hepatic drug metabolizing enzymes, such as cytochrome P-450, cytochrome b5, aminopyrine demethylase and aniline hydroxylase.