Journal of Clinical Endocrinology & Metabolism, Vol 81, 1832-1840, Copyright © 1996 by Endocrine Society

ARTICLES

Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site- - a clinical research center study

AW Meikle, S Arver, AS Dobs, SW Sanders, L Rajaram and NA Mazer
Department of Medicine, University of Utah, Salt Lake City 84132, USA.

As part of a phase III multicenter study, the pharmacokinetics and metabolism of a permeation-enhanced testosterone (T) transdermal (TTD) system and the influence of application site were investigated in 34 hypogonadal men (21-65 yr of age). After an 8-week androgen washout period, two TTD systems were applied to the back for 24 h. Serum concentrations of total T, bioavailable testosterone (BT), dihydrotestosterone (DHT), and estradiol (E2) increased from hypogonadal levels into the respective normal physiological ranges and declined to baseline levels within 24 h after system removal. Peak concentrations occurred approximately 8 h after application for T and BT and at 13 h for DHT and E2. The baseline-subtracted time-average steady state concentrations (C'ss) for T and BT were 18.1 +/- 7.49 (+/- SD) and 9.08 +/- 3.99 nmol/L, respectively. DHT/T and E2/T ratios, derived from the C'ss values, were 0.063 +/- 0.018 and 0.0033 +/- 0.0018, comparable to the precursor-product conversion ratios reported in healthy men. The estimated half-lives of each hormone were: T, 1.29 +/- 0.71 h; BT, 1.21 +/- 0.75 h; DHT, 2.83 +/- 0.97 h; and E2, 3.53 +/- 1.93 h. The influence of application site was then evaluated by applying two TTD systems for 24 h to the abdomen, back, chest, shin, thigh, or upper arm, according to a sequential cross-over design. Hormone profiles were qualitatively similar at each site, but C'ss values showed significant differences (by ANOVA, P < 0.0001). Based on the BT levels, the rank ordering of the sites were: back > thigh > upper arm > abdomen > chest > shin. DHT/T and E2/T ratios showed negligible site to site variation and were comparable to the results from the initial study. Estimates of T input, based on hormone levels and analysis of the systems used, averaged 4-5 mg/day for the abdomen, back, thigh, and upper arm and were lower and more variable for the chest and shin. Individual C'ss values for T and BT increased linearly with the T input rates (derived from used system analysis) across all studies (n = 235; r = 0.564 for T and r = 0.754 for BT). From these data, T and BT clearance rates were estimated for each patient, averaging 1248 +/- 518 and 2435 +/- 778 L/day, respectively. T clearance rates were proportional to the BT/T ratio (nonsex hormone- binding globulin-bound fraction). On the basis of these studies, the optimal sites of TTD system application were identified as the back, thigh, upper arm, and abdomen

This article has been cited by other articles:

				M. Wald, R. B. Meacham, L. S. Ross, and C. S. Niederberger Testosterone Replacement Therapy for Older Men J Androl, March 1, 2006; 27(2): 126 - 132. [Full Text] [PDF]

				C. Wang, R. Swerdloff, M. Kipnes, A. M. Matsumoto, A. S. Dobs, G. Cunningham, L. Katznelson, T. J. Weber, T. C. Friedman, P. Snyder, et al. New Testosterone Buccal System (Striant) Delivers Physiological Testosterone Levels: Pharmacokinetics Study in Hypogonadal Men J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3821 - 3829. [Abstract] [Full Text] [PDF]

				A. Mayo, H. Macintyre, A. M. Wallace, and S. F. Ahmed Transdermal Testosterone Application: Pharmacokinetics and Effects on Pubertal Status, Short-Term Growth, and Bone Turnover J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 681 - 687. [Abstract] [Full Text] [PDF]

				A. M. Kenny, S. Bellantonio, C. A. Gruman, R. D. Acosta, and K. M. Prestwood Effects of Transdermal Testosterone on Cognitive Function and Health Perception in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2002; 57(5): M321 - 325. [Abstract] [Full Text]

				H. A. Feldman, C. Longcope, C. A. Derby, C. B. Johannes, A. B. Araujo, A. D. Coviello, W. J. Bremner, and J. B. McKinlay Age Trends in the Level of Serum Testosterone and Other Hormones in Middle-Aged Men: Longitudinal Results from the Massachusetts Male Aging Study J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 589 - 598. [Abstract] [Full Text] [PDF]

				A. M. Kenny, K. M. Prestwood, C. A. Gruman, K. M. Marcello, and L. G. Raisz Effects of Transdermal Testosterone on Bone and Muscle in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2001; 56(5): 266M - 272. [Abstract] [Full Text]

				A. S. Dobs, P. S. Bachorik, S. Arver, A. W. Meikle, S. W. Sanders, K. E. Caramelli, and N. A. Mazer Interrelationships among Lipoprotein Levels, Sex Hormones, Anthropometric Parameters, and Age in Hypogonadal Men Treated for 1 Year with a Permeation-Enhanced Testosterone Transdermal System J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1026 - 1033. [Abstract] [Full Text]

				R. S. Swerdloff, C. Wang, G. Cunningham, A. Dobs, A. Iranmanesh, A. M. Matsumoto, P. J. Snyder, T. Weber, J. Longstreth, and N. Berman Long-Term Pharmacokinetics of Transdermal Testosterone Gel in Hypogonadal Men J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4500 - 4510. [Abstract] [Full Text]

				F. J. Hayes Testosterone--Fountain of Youth or Drug of Abuse? J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3020 - 3023. [Full Text]

				C. Wang, R. S. Swerdloff, A. Iranmanesh, A. Dobs, P. J. Snyder, G. Cunningham, A. M. Matsumoto, T. Weber, and N. Berman the Testosterone Gel Study Group Transdermal Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and Body Composition Parameters in Hypogonadal Men J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2839 - 2853. [Abstract] [Full Text]

				C. Wang, N. Berman, J. A. Longstreth, B. Chuapoco, L. Hull, B. Steiner, S. Faulkner, R. E. Dudley, and R. S. Swerdloff Pharmacokinetics of Transdermal Testosterone Gel in Hypogonadal Men: Application of Gel at One Site Versus Four Sites: A General Clinical Research Center Study J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 964 - 969. [Abstract] [Full Text]

				A. S. Dobs, D. R. Hoover, M.-C. Chen, and R. Allen Pharmacokinetic Characteristics, Efficacy, and Safety of Buccal Testosterone in Hypogonadal Males: A Pilot Study J. Clin. Endocrinol. Metab., January 1, 1998; 83(1): 33 - 39. [Abstract] [Full Text]

				D. H. Catlin, C. K. Hatton, and S. H. Starcevic Issues in detecting abuse of xenobiotic anabolic steroids and testosterone by analysis of athletes' urine Clin. Chem., July 1, 1997; 43(7): 1280 - 1288. [Abstract] [Full Text] [PDF]