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 ...

The development and validation of methods for determining concentrations of the antipsychotic drug asenapine (ASE) and three of its metabolites [N-desmethylasenapine (DMA), asenapine-N(+) -glucuronide (ASG) and 11-O-sulfate-asenapine (OSA)] in human plasma using LC-MS/MS with automated solid-phase extraction is described. The three assessment methods in human plasma were found to be acceptable for quantification in the ranges 0.0250-20.0 ng/mL (ASE), 0.0500-20.0 ng/mL (DMA and OSA) and 0.250-50.0 ng/mL (ASG).

SummaryObjective Andriol® Testocaps® is a new oral formulation of testosterone undecanoate (TU) for treatment of hypogonadism. As TU is taken up by the intestinal lymphatic system, both the presence and the composition of food influence the absorption. The aim of this study was to investigate the effect of food composition on the pharmacokinetics of oral TU. Design An open-label, single-centre, four-way crossover study. With a washout period of 6-7 days, 80 mg TU was administered in the morning 5 min after consuming each of four different meals in a randomized order (A: 230 kcal, 0·6 g lipid; B: 220 kcal, 5 g lipid; C: 474 kcal, 19 g lipid; D: 837 kcal, 44 g lipid).Patients Twenty-four postmenopausal volunteers. Measurements Serial blood samples were collected until 24 h after dosing to determine testosterone and dihydrotestosterone (DHT) by gas chromatography-mass spectroscopy (GC-MS). Results The bioavailability of testosterone after a low-calorie meal containing 0·6 g lipid or 5 g lipid was relatively low, the area under the concentration-time curve (AUC 0-tlast ) for testosterone being 30·7 and 43·5 nmol h/l, respectively. The bioavailability of testosterone after a meal containing 19 g lipid was considerably higher (AUC 0-tlast = 146 nmol h/l), whereas increasing the lipid content to 44 g lipid did not further increase the bioavailability of testosterone (AUC 0-tlast = 154 nmol h/l). Conclusion Approximately 19 g of lipid per meal efficiently increases absorption of testosterone from oral TU. Therefore, coadministration with a normal rather than a fatty meal is sufficient to increase serum testosterone levels when using oral TU.

To support the evaluation of the pharmacokinetic parameters of asenapine (ASE) in urine, we developed and validated online solid-phase extraction high-performance liquid chromatography methods with tandem mass spectrometry detection (SPE-LC-MS/MS) for the quantification of ASE and two of its major metabolites, N-desmethylasenapine (DMA) and asenapine-N⁺-glucuronide (ASG). The linearity in human urine was found acceptable for quantification in a concentration range of 0.500-100 ng/mL for ASE and DMA and 10.0-3000 ng/mL for ASG, respectively.

Background: Assessment of testosterone undecanoate's (TU) presence in the functional compartments of the male reproductive tract has never been performed despite the evidence that its documented beneficial effect in male infertility might be mediated through an epididymal action and this study was set to examine this possibility. Materials and methods: In 18 normozoospermic volunteers TU has been administered (40 mg t.i.d.) for 6 days with serum measurements of TU, total testosterone (T), DHT, E2, SHBG, FSH, LH, and PRL before and at the end of medication. Steroid hormones (T, E2, and TU) were also assayed in seminal plasma. In a selected group of 7 men with previously diagnosed non-obstructive azoospermia TU, T, and E2 were assayed in the extracts of testicular biopsy material taken before ICSI and at the end of the same medication. Results: A marked rise of serum DHT (average 148%, P < 0.001) has been found after treatment, whereas T, E2, FSH, LH, SHBG, and PRL did not significantly change. Measurable amounts of TU were found in the serum of all men but only in 6 cases in seminal plasma (11.1 ± 8.0 ng/mL) and all of them in semen delivered 7-8 h after the last TU capsule was taken. In dilution fluid from testicular tissue extracts, no detectable amounts of TU were found whereas mean values of 92.5 ± 54.3 pg/mL and 43.8 ± 16.3 ng/mL for E2 and T were observed. Positive correlations among TU and E2, T or DHT concentrations were found in serum samples (P < 0.01, 0.02, and 0.002) as well as between E2 and T (P < 0.01), E2 and DHT (P < 0.001), or T and DHT (P < 0.001). Conclusion: It is concluded that TU was identified and measured for the first time in seminal plasma of a fair percentage (33%) of men on this medication and was associated in all men with a marked rise of DHT concentration, a known epididymal function promoter, in the absence of an effect on pituitary and gonadal activity. On this evidence, it appears that a beneficial effect of TU on epididymal function may be a distinct possibility.Keywords Testosterone undecanoate · Dihydrotestosterone · Seminal plasma · Peripheral blood Résumé L'évaluation de la présence d'undécanoate de testostérone (TU) dans les compartiments fonctionnels de l'appareil reproducteur masculin n'a jamais été réalisée malgré le fait que son effet bénéfique documenté dans l'infertilité masculine pourrait être médié par une action épididymaire; cette étude avait comme but d'examiner cette possibilité. Chez 18 volontaires normozoospermiques, du TU a été administré (40 mg 3x/j) pendant 6 jours avec des dosages sériques de TU, testostérone totale (T), DHT, E 2 , SHBG, FSH, LH et PRL avant et à la fin du traitement. Les hormones stéroïdes (T, E 2 , TU) ont également été mesurées dans le plasma séminal. Dans un groupe de 7 hommes ayant une azoospermie non obstructive préalablement diagnostiquée, les concentrations de TU, T et E2 ont été mesurées dans des fragments de tissu de la biopsie testiculaire effectuée avant ICSI et à la fin du même traitement. Une augmentation marquée des taux sér...