Metabolism of 14C-moxisylyte after percutaneous application in hairless rat.
The pharmacokinetics of 14C-thymoxamine (4-(2-dimethylaminoethoxy)-5-isopropyl-2-methyl phenyl acetate, CAS 54-32-0, moxisylyte, Carlytène) were studied in female hairless rats following different administration routes: oral, intravenous or percutaneous. After percutaneous administration, the half-life of elimination of 14C-thymoxamine and its metabolites was longer (t 1/2 = 15 h) than after oral or intravenous administration (t 1/2 = 9 h). The penetration/resorption phenomenon of thymoxamine base mainly located in the horny layer could explain the high value of the pseudo half-life of elimination observed after percutaneous administration. Due to the absorption slower than elimination, this special pharmacokinetics had to be considered as a flip-flop model. The type and proportions of thymoxamine metabolites recovered in plasma varied according to the route of administration. The unconjugated metabolites, desacetyl-thymoxamine (DAT) + desacetyl-desmethyl-thymoxamine (DMAT), were observed only after intravenous or percutaneous administration, they represented 12% and 15%, respectively. They were never observed after oral administration suggesting the existence of a hepatic first-pass metabolism. The other metabolites observed were sulphate conjugates and glucuronides of DAT + DMAT. The values of sulfoconjugates were constant with each administration route (21%), whereas glucuronides increased with oral administration. In conclusion, the pharmacokinetics of percutaneous thymoxamine presented two main features: the drug absorption was high and durable (t 1/2 = 15 h); the cutaneous application allowed to avoid the hepatic first-pass metabolism.
Neau
B
B
ADME Bioanalyses, Parc de Haute Technologie de Sophia-Antipolis, Mougins, France.
Roux
J
J
Marty
J P
JP
D000287:Administration, Topical; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D013948:Moxisylyte / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism; D014018:Tissue Distribution
D000317:Adrenergic alpha-Antagonists; D005965:Glucuronates; D013431:Sulfates; D013948:Moxisylyte