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Article / 1998

Pharmacokinetics, protein binding, and metabolic profile of 3H-icometasone enbutate following intravenous, oral, and intratracheal administrations to Sprague-Dawley rats

Authors:
  • Patrick Duchene
  • Bernard Neau
  • Agnes Gronfier
  • Yves Firmin
  • Peter Villax
  • Sylvie Saivin
  • Georges Houin
Source:
Arzneim.-Forsch. (1998), 48(4), 371-378

Absorption, distribution, and excretion of 3H-icometasone enbutate (9.alpha.-chloro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna- 1,4-diene-3,20-dione, 17-butyrate, 21-acetate, CAS 103466-73-5 CL09) were studied in male and female Sprague-Dawley rats after a single dose administration by i.v. (1 mg/kg), oral, and intratracheal (2 mg/kg) routes. The metabolic profile after the different routes and protein binding were also detd. Independent of the route, the radioactivity was mainly excreted in feces. Less than 10% of the dose were excreted in urine. The majority of the administered doses was recovered within 24 h postdose, and the total recovery of the doses administered was obtained. After oral and i.v. administration to bile-duct cannulated rats, most of the radioactivity was excreted in the bile (80% of the administered dose) and some radioactivity was found in the feces. It can thus be concluded that some intestinal secretion occurred. After oral administration, mean max. blood concns. were obtained about 0.75 h postdose. For the intratracheal route, the radioactive dose administered was too low to det. precise blood pharmacokinetic parameters. However, the distribution study results allowed us to conclude that the drug was absorbed 1st from the lungs and then from the gastrointestinal tract. Immediately after the i.v. injection, the liver, the kidneys, the small intestine and its contents, and the carcass presented the highest levels of radioactivity. 168 H postdose, low radioactivity was still measurable in these organs. In other tissues, the radioactivity decreased reaching the limit of quantification 72 h postdose. After oral administration, the max. concns. were obsd. 1 h after administration in the liver, the small intestine and its contents. Then the radioactivity decreased in most of the tissues but a slight increase at 72 and/or 120 h postdose was noted in large intestine contents, carcass, lungs, eyes. After intratracheal administration, the max. radioactivity was obsd. in lungs and trachea. A few minutes later the radioactivity reached the gastrointestinal tract. The protein binding study showed a saturable binding in rat and human blood plasma without notable differences between the 2 species. The binding on human serum albumin was not saturable with a total binding capacity of 7.48 .mu.mol/L, suggesting that other proteins were involved in CL09 binding. This binding was reversible. CL09 was extensively metabolized since no unchanged CL09 was recovered in bile or urine and at least 9 metabolites were detected. The profiles were different according to the route of administration.