Testosterone pharmacokinetics

Yin A, Alfadhli E, Htun M, Dudley R, Faulkner S, Hull L et al. Dietary fat modulates the testosterone pharmacokinetics of a new self-emulsifying formulation of oral testosterone undecanoate in hypogo-nadalmen. JAndrol. 33(6) (2012) 1282-1290. 

Wang C, Swerdloff R, Kipnes M, Matsumoto AM, Dobs AS, Cunningham G, Katznelson L, Weber TJ, Friedman TC, Snyder P, and Levine HL (2004) New testosterone buccal system (Striant) delivers physiological testosterone levels Pharmacokinetics study in hypogonadalmen. J. Clin. Endocrinol. Metab. 89 3821— 3829. 

Mechanism of Action A synthetic testosterone derivative that promotes growth and development of male sex organs, maintains secondary sex characteristics in androgen-deficient males. Therapeutic Effect Androgenic and anabolic actions. Pharmacokinetics Well absorbed from fhe gastrointestinal (GI) tract. Protein binding 94%-97%. Metabolized in liver. Primarily excreted in urine. Unknown if removed by hemodialysis. Half-life 5-13 hr. 

Ross RJM, Jabbar A, Jones TH, Roberts B, Dunkley K, Hall J, Long A, Levine H, Cullen DR. Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men. Eur J Endocrinol 2004 150 57-63. 

Dobs AS, Matsumoto AM, Wang C, Kipnes MS. Shortterm pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men. Curr Med Res Opin 2004 20 729-38. 

Tauber, U., et al. 1986. Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone. Eur J Drug Metab Pharmacokinet 11 145. 

Oishi S. 1989b. Effects of co-administration of di(2-ethylhexyl)phthalate and testosterone on several parameters in the testis and pharmacokinetics of its mono-cb-esterified metabolite. Arch Toxicol 63 289-295. 

Initially, when spirorenone was tested in low doses on a male human, an unambiguous reduction of the subject s testosterone level was detected. The reason for this change was provided by pharmacokinetic monitoring, wherein it was realized that in humans and in monkeys, unlike other species, spirorenone was metabolized exclusively to 1,2-dihydrospirorenone (drospirenone), by the action of a A -hydrase (Fig. 17.5). 

Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity, see below) it is widely distributed in tissues but concentrations in CSF and urine are low its action is terminated by metabolism by cytochrome P450 3A (CYP 3A) (t) 8 h). Ketoconazole is effective by mouth for systemic mycoses (see Table 14.2) but has been superseded by fluconazole and itraconazole for many indications largely on groimds of improved pharmacokinetics, imwanted effect profile and efficacy. Impairment of steroid synthesis by ketoconazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer. 

Testosterone (T) Male (25-69) Upper buttocks, upper arm, back D-Trans (Alza Corp.) Pharmacokinetic parameters Similar pharmacokinetic profiles between sites ... 

Testosterone (T) Female Abdomen, forearm MDTS spray solution Pharmacokinetic parameters Average and maximum serum concentrations of free and total T were significantly higher after application to the forearm compared to the abdomen V... 

R. S. Pharmacokinetics of transdermal testosterone gel in hypogonadal men apphcation of gel at one site versus four sites a general chnical research center study. J. Clin. Endocrinol. Metab. 2000, 85, 964—969. 

Humberstone, A.J. Evans, A.M. Davis, S.R. A Comparative Study of the Pharmacokinetics of Testosterone (T) Following Administration of a Metered-Dose Transdermal Spray (MDTS(R)) to the Abdomen or Forearm in Healthy Postmenopausal Women with Low Serum Testosterone, Endocrine Society s 85th Annual General Meeting, Philadelphia, USA, 2002. 

Yu, Z. Gupta, S.K. Hwang, S.S. Cook, D.M. Duckett, M.J. Atkinson, L.E. Transdermal testosterone administration in hypogonadal men comparison of pharmacokinetics at different sites of application and at the first and fifth days of application. J. Clin. Pharmacol. 1997, 57, 1129-1138. Zobrist, R.H. Quan, D. Thomas, H.M. Stanworth, S. Sanders, S.W. Pharmacokinetics and metabolism of transdermal oxybutynin in vitro and in vivo performance of novel delivery system. Pharm. Res. 2003, 20, 103-109. Marzulli, E.N. Barriers to skin penetration. J. Invest. Dermatol. 1962, 39, 387-389. 

Given the above preclinical observations, patients in a clinical study were monitored closely during treatment (including measurement of testosterone, luteinizing hormone, follicle-stimulating hormone levels, alkaline phosphatase, and serum vitamin A concentrations). This phase I clinical study of TAG-101 was conducted to determine the safety, toxicity, and pharmacokinetics of this agent in patients with advanced cancer. Currently, the drug is in a phase I/II clinical trial for advanced hepatocellular carcinoma. 

These improved pharmacokinetic and side-effect profiles for SARMs versus steroidal androgens are associated with potent, tissue-selective effects in therapeutic target tissues. Hyperanabolic effects in skeletal muscle have been seen for SARMs in rat for numerous molecules [90, 151, 176, 184] with myoanabolic effects in castrated rats in the range of 100-150% compared to testosterone. These effects have also been seen in human trials as manifested by increases in LBM and improvements in physical performance tests (stair climb time [96]). Osteoanabolic effects have also been demonstrated in rats [95, 128, 151] and monkeys [130] for numerous molecules however, only limited clinical trials data have been released in human [128],... 

Mazer, N Bell, D., Wu, J., Fischer, J., Cosgrove, M. and Eilers, B. (2005) Comparison of the steady-state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men. Journal of Sexual Medicine, 2, 213-226. 

FIGURE 58-6 Pharmacokinetic profiles of three testosterone preparations during their chronic administration to hypogonadal men. Doses of each were given at time 0. Dashed lines indicate range of normal levels. 

Schwahn, M., Nagaraja, N. V, and Cohen, A. R, Population pharmacokinetic/phar-macodynamic modeling of cetrorelix, a novel LH-RH antagonist, and testosterone in rats and dogs, Pharm. Res., 17(3) 328-335, 2000. 

Pechstein, B. et al.. Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers, J. Clin. Pharmacol., 40(3) 266-274, 2000. 

Murayama N, Nakamura T, Saeki M, Soyama A, Saito Y, Sai K, Ishida S, Nakajima O, Itoda M, Ohno Y, Ozawa S, Sawada J (2002) CYP3A4 gene polymorphisms influence testosterone 6j8-hydroxylation. Drug Metab Pharmacokinet 17 150-156... 

Lee SJ, Goldstein JA (2012) Comparison of CY-P3A4 and CYP3A5 the effects of cytochrome and NADPH-cytochrome P450 reductase on testosterone hydroxylation activities. Drug Metab Pharmacokinet 27 663-667... 

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