Endogenous and exogenous testosterone levels after administration of deuterium-labelled testosterone propionate in hypogonadotropic hypogonadism.

Fujioka, Minoru; Shinohara, Yoshihiko; Baba, Shigeo; Irie, Minoru; Inoue, Kazuko

doi:10.1248/cpb.37.3100

Cited by 4 publications

(2 citation statements)

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“…In the lymph duct cannulated dog, the apparent bioavailability calculated from the ratio of the dose normalized systemic serum AUC values after oral and i.v. administration (determined using a stable TU isotope, which is not expected to exhibit an in vivo isotope effect; Baba et al, 1979Baba et al, , 1980Shinohara et al, 1980Shinohara et al, , 1988Fujioka et al, 1986Fujioka et al, , 1989Shinohara and Baba, 1990) is equivalent to the fraction of the dose systemically available after absorption via the portal vein.…”

Section: Discussionmentioning

confidence: 99%

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

Shackleford¹,

Faassen²,

Houwing³

et al. 2003

J Pharmacol Exp Ther

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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 (ϮS.E., n ϭ 4) absolute bioavailability of TU was 3.25 Ϯ 0.48 and 2.88 Ϯ 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 Ϯ 1.6 and 84.1 Ϯ 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.The oral administration of testosterone (T) is ineffective in the treatment of male androgen deficiency syndromes because T is subject to almost quantitative presystemic firstpass metabolism mediated by the gut wall and liver (Daggett et al., 1978). Conversely, the lipophilic ester prodrug testosterone undecanoate (TU) demonstrates androgenic activity after oral administration to rats and humans (Hirschhauser et al., 1975;Maisey et al., 1981;Skakkebaek et al., 1981). Because oral administration of TU results in the appearance of TU (and the metabolite 5␣-dihydrotestosterone undecanoate; DHTU) in lymph of thoracic duct-cannulated rats Noguchi et al., 1985) and humans (for whom a thoracic duct cannula was inserted after neck dissection surgery; Horst et al., 1976), the androgenic activity of orally administered TU is generally attributed to T (and 5␣-dihydrotestosterone; DHT) formed during the systemic metabolic elimination of TU, which escaped the presystemic first-pass effect due to intestinal lymphatic absorption and transport Horst et al., 1976).Although it is accepted that lymphatic absorption of TU likely contributes to systemic T exposure after oral TU administration, the extent of that contribution has not been quantitatively determined. Indirect evidence of lymph transport of TU in humans was reported where the systemic exposure of T increased after oral TU administration in the fed state, compared with administration in the fasted state (Frey et al., 1979;Bagchus et al., 2003). However, human studies cannot determine ...

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Section: Discussionmentioning

confidence: 99%

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

Shackleford¹,

Faassen²,

Houwing³

et al. 2003

J Pharmacol Exp Ther

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“…In fact, the observed PK profile after a TNG dose is a sum of all sources of testosterone [20, 21]; exogenous and endogenous sources were not independently quantifiable in this study. When exogenous testosterone was administered, there was a suppression of LH and testosterone production.…”

Section: Discussionmentioning

confidence: 95%

Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels

Gronski¹,

Grober

Gottesman

et al. 2019

Journal of the Endocrine Society

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Objective Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option. Materials and Methods Patients with testosterone deficiency (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels on days 30 and 90, along with efficacy measurements, which were analyzed by comparison with baseline values. Baseline and/or predose TT values were used for patient stratification. Results Prestudy and predose endogenous testosterone concentrations correlated. The maximal concentration of TT was nearly identical across all cohorts at days 30 and 90, whereas the average concentration over 24 hours had a slight positive dependence relative to predose levels. LH levels remained in the normal range but were decreased more in patients with higher starting baseline levels. These findings indicate that TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period. Patients with the lowest endogenous testosterone levels received maximum exposure impact from each TNG dose. Patients with severe testosterone deficiency had similar efficacy improvements as the remainder of the study population. Conclusion All testosterone-deficient cohorts were successfully treated with TNG.

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Stable isotope methodology in the pharmacokinetic studies of androgenic steroids in humans

Shinohara¹,

Baba²

1990

Steroids

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Endogenous and exogenous testosterone levels after administration of deuterium-labelled testosterone propionate in hypogonadotropic hypogonadism.

Cited by 4 publications

References 0 publications

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

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

Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels

Stable isotope methodology in the pharmacokinetic studies of androgenic steroids in humans

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