Pharmacokinetics, protein binding and metabolic profile of 3H-icometasone enbutate following intravenous, oral and intratracheal administrations to Sprague-Dawley rats.
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 intravenous (1 mg/kg), oral and intratracheal (2 mg/kg) routes. The metabolic profile after the different routes and protein binding were also determined. Independent of the route, the radioactivity was mainly excreted in faeces. 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 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 occurred. After oral administration, mean maximum blood concentrations were obtained about 0.75 h postdose. For the intratracheal route, the radioactive dose administered was too low to determine precise blood pharmacokinetic parameters. However, the distribution study results allowed us to conclude that the drug was absorbed first from the lungs and then from the gastrointestinal tract. Immediately after the intravenous 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 maximum concentrations were observed 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 maximum radioactivity was observed 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 plasma without notable differences between the two species. The binding on human serum albumin was shown to be non saturable with a total binding capacity of 7.48 +/- 1.83 mumol/l, suggesting that other proteins were involved in CL09 binding. This binding was demonstrated to be reversible. CL09 was extensively metabolized since no unchanged CL09 was recovered in bile or urine and at least nine metabolites have been detected. The profiles seemed to be different according to the route of administration.
Duchêne
P
P
ADME Bioanalyses, Mougins, France.
Giudicelli
M D
MD
Neau
B
B
Gronfier
A
A
Firmin
Y
Y
Villax
P
P
Saivin
S
S
Houin
G
G
D000284:Administration, Oral; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D005260:Female; D007275:Injections, Intravenous; D007442:Intubation, Intratracheal; D008297:Male; D011245:Pregnadienes / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D018927:Anti-Asthmatic Agents; D011245:Pregnadienes; C112801:icometasone enbutate