PHARMACOKINETICS, PROTEIN-BINDING AND METABOLIC PROFILE OF H-3-ICOMETASONE ENBUTATE FOLLOWING INTRAVENOUS, ORAL AND INTRATRACHEAL ADMINISTRATIONS TO SPRAGUE-DAWLEY RATS

Absorption, distribution and excretion of H-3-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) wer e studied in male and female Sprague-Dawley rats after a single dose a dministration by intravenous (1 mg/kg), oral and intratracheal (2 mg/k g) routes. The metabolic profile after the different routes and protei n binding were also determined. Independent of the route, the radioact ivity was mainly excreted in faeces. Less than 10 % of the dose were e xcreted in urine. The majority of the administered doses was recovered within 24 h postdose, and the total recovery of the doses administere d was obtained. After oral and intravenous 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 faeces. It can thus be concluded that some intestinal secretion occur red. After oral administration, mean maximum blood concentrations were obtained about 0.75 h postdose. For the intratracheal route, the radi oactive dose administered was too low to determine precise blood pharm acokinetic parameters. However, the distribution study results allowed us to conclude that the drug was absorbed first from the lungs and th en from the gastrointestinal tract. Immediately after the intravenous injection, the liver, the kidneys, the small intestine and its content s 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 quant ification 72 h postdose. After oral administration, the maximum concen trations were observed 1 h after administration in the liver, the smal l 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 intratr acheal administration, the maximum radioactivity was observed in lungs and trachea. A few minutes later the radioactivity reached the gastro intestinal tract. The protein binding study showed a saturable binding in rat and human plasma without notable differences between the two s pecies. The binding on human serum albumin was shown to be non saturab le with a total binding capacity of 7.48 +/- 1.83 mu mol/l, suggesting that other proteins were involved in CL09 binding. This binding was d emonstrated to be reversible. CL09 was extensively metabolized since n o unchanged CL09 was recovered in bile or urine and at least nine meta bolites have been detected. The profiles seemed to be different accord ing to the route of administration.