TRANSDERMAL TESTOSTERONE DELIVERY IN CASTRATED YUCATAN MINIPIGS - PHARMACOKINETICS AND METABOLISM

The feasibility of using the castrated Yucatan minipig as a hypogonada l animal model to investigate the transdermal controlled systemic deli very of testosterone was studied. During a 24 h application of a testo sterone transdermal delivery device (T-TDD), serial blood samples were withdrawn from the minipigs, without anesthesia, at predetermined tim e intervals and the plasma concentrations of testosterone as well as i ts major metabolites, dihydrotestosterone and estradiol, were assayed by radioimmunoassay. The compartmental pharmacokinetic modeling analys is of the plasma profiles of total testosterone indicated that as much as 92% of the total testosterone dose released from the T-TDD had bee n delivered transdermally into the systemic circulation during the ini tial rapid input period (the first 11 h of the application), while onl y 8% was delivered during the slow input period (up to 23 h). Good cor relation was observed between the in vivo input doses [1.9 (+/-0.2), 4 .8 (+/-0.2) and 6.4 (+/-0.5) mg/day], determined by the Wagner-Nelson equation, and the daily doses released [1.9+/- (0.2), 4.7 (+/-0.2) and 6.6 (+/-0.5) mg/day, respectively, for 1, 2, and 3 units of T-TDD]. W hile the in vivo rate of input in the castrated minipigs was observed to be similar to that in hypogonadal men treated with the T-TDD during the first 8 h period, the input rate was found to be slower during th e last 12 h. The agreement could suggest that the mechanism for the tr ansdermal systemic delivery of testosterone in the castrated minipig c ould be similar to that in the hypogonadal men. However, the plasma te stosterone profiles attained in the castrated minipigs were observed t o be similar to, but slightly lower than that in the hypogonadal men r eported in the literature. The Delta C-max (baseline normalized peak p lasma concentration) and Delta C-avg (baseline normalized average plas ma concentration) data in the castrated minipigs were 40 and 44%, resp ectively, of that in hypogonadal men. The similar to 2.4 fold lower va lues in Delta C-max and Delta C-avg data could result from the differe nce in the clearance rate of testosterone which is similar to 2.8 fold higher in minipigs than in the human. Despite the difference in clear ance rate, the castrated minipigs could be a suitable large animal mod el for studying the pharmacokinetics of testosterone delivered transde rmally in humans with hypogonadism. (C) 1998 Elsevier Science B.V.