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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Contribution of Lymphatically Transported Testosterone Undecanoate to the Systemic Exposure of Testosterone after Oral Administration of Two Andriol Formulations in Conscious Lymph Duct-Cannulated Dogs

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria, Australia (D.M.S., C.J.H.P., W.N.C.); Department of Pharmaceutics, NV Organon, BH Oss, The Netherlands (W.A.F.); Department of Drug Metabolism and Kinetics, NV Organon, BH, Oss, The Netherlands (N.H.); Department of Drug Metabolism and Kinetics, Organon Development GmbH, Waltrop, Germany (H.L.); and Department of Veterinary Sciences, The University of Mebourne, Werribee, Victoria, Australia (C.J.H.P.)

Orally administered testosterone (T) is ineffective in the treatment of male androgen deficiency syndromes due to extensive presystemic first-pass metabolism. In contrast, the lipophilic long-chain ester testosterone undecanoate (TU) exhibits androgenic activity that has been attributed to formation of T via systemic hydrolysis of lymphatically transported TU. However, there are no definitive data regarding the oral bioavailability of TU or the extent to which lymphatically transported TU contributes to the systemic availability of T after oral TU administration. This report describes the application of stable isotope methodology in a thoracic lymph duct-cannulated dog model to study the oral bioavailability and lymphatic transport of TU after postprandial administration. When administered as either Andriol or Andriol Testocaps, the mean (±S.E., n = 4) absolute bioavailability of TU was 3.25 ± 0.48 and 2.88 ± 0.88%, respectively, and lymphatically transported TU accounted for between 91.5 and 99.7% of the systemically available ester. Model-independent pharmacokinetic analysis indicated that 83.6 ± 1.6 and 84.1 ± 8.2% of the systemically available T, resulting from Andriol or Andriol Testocaps, respectively, was due to systemic hydrolysis of lymphatically transported TU. These data demonstrate that intestinal lymphatic transport of TU produces increased systemic exposure of T by avoiding the extensive first-pass effect responsible for the inactivation of T after oral administration.

Address correspondence to: Dr. William N. Charman, Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia. E-mail: bill.charman{at}vcp.monash.edu.au

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