Pharmacokinetic studies of testosterone propionate using gas chromatography/mass spectrometry/selected Ion monitoring

Shinohara, Yoshihiko; Fujioka, Minoru; Baba, Shigeo

doi:10.1002/bms.1200160144

Cited by 7 publications

(1 citation statement)

References 12 publications

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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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Detection of testosterone esters in human plasma

et al. 1995

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The detection of testosterone misuse in sports is currently based on the urinary testosterone to epitestosterone ratio, although in some rare instances physiological or pathological conditions could compromise the application of this general criterion. The detection in the body of traces of the unchanged testosterone esters really ingested would offer unequivocal confirmation of testosterone administration. In this work, the detectability of testosterone esters in humans was studied. Liquid-liquid extraction of human blood plasma and appropriate derivatization of nine testosterone esters are described. Different acyl (trifluoroacetyl, pentafluoropropionyl and heptafluorobutyryl) and trimethylsilyl derivatives were studied. The trimethylsilyl derivatives appear to be the best for screening purposes based on the characteristics of their mass spectra, with abundant molecular ions in the high-mass range. They also offered good conditions for tandem mass spectrometric analysis, needed to achieve the required sensitivity after oral administration of the drugs. The method was successful in the detection and determination of intramuscularly administered testosterone propionate and testosterone enanthate and orally ingested testosterone undecanoate.

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Applications of isotope dilution‐mass spectrometry in clinical chemistry, pharmacokinetics, and toxicology

Leenheer

Thienpont

1992

Mass Spectrometry Reviews

109

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Pharmacokinetic studies of testosterone propionate using gas chromatography/mass spectrometry/selected Ion monitoring

Cited by 7 publications

References 12 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

Detection of testosterone esters in human plasma

Applications of isotope dilution‐mass spectrometry in clinical chemistry, pharmacokinetics, and toxicology

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