Pulmonary delivery of detirelix by intratracheal instillation and aerosol inhalation in the briefly anesthetized dog.

Pulmonary delivery of the decapeptide detirelix was studied in briefly anesthetized dogs and the pharmacokinetics were examined following intravenous administration, intratracheal instillation, and aerosol inhalation. Detirelix administrations to the lung gave plasma profiles that were extended over two days, and that differed markedly from those of similarly sized peptides. Absorption from the lung after instillation was slow (Tmax = 6.5 +/- 3.6 h) with a relative bioavailability of 29 +/- 10%. Administration of detirelix-containing aerosols resulted in similar plasma profiles as for administration by instillation. Compartmental and non-compartmental methods of pharmacokinetic analysis indicated no faster absorption from aerosols than from instilled solutions; an absorption rate limiting process may be an explanation. Plasma profiles were not affected by the use of detirelix liquid crystal favoring formulations or destabilizing formulations, and suggested that in situ liquid crystal formation was not an explanation for the slow absorption. No significant changes in pharmacokinetics or systemic uptake were observed during the five-month period of repeated pulmonary administrations. Histopathologic examination revealed the lungs to be essentially normal.

Concordant suppression of serum immunoreactive luteinizing hormone (LH), follicle-stimulating hormone, alpha subunit, bioactive LH, and testosterone in postmenopausal women by a potent gonadotropin releasing hormone antagonist (detirelix).

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P less than 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption and metabolism of nafarelin, a potent agonist of gonadotropin-releasing hormone.

Nafarelin, a potent gonadotropin-releasing hormone (GnRH) agonist, was absorbed rapidly into systemic circulation (time to reach peak concentration, 20 to 40 minutes) after intranasal but not after sublingual or vaginal administration. Serum elimination half-life was about 2 hours. Nasal absorption of nafarelin was increased by increasing the concentration of the drug in the dose solution and incorporating sodium glycocholate into the nasal formulation. An optimal formulation providing maximum nasal absorption of nafarelin was one containing 1.75 mg nafarelin per ml and 2% sodium glycocholate. Bioavailability of this nasal formulation relative to a single subcutaneous dose averaged 21%. The metabolism and excretion of nafarelin were determined in three subjects after subcutaneous administration of [14C]-nafarelin. Radioactivity was excreted in approximately equal amounts in urine and stool. Six metabolites accounted for most of the radioactivity in urine. Four metabolites were short peptide fragments of nafarelin and the other metabolites were naphthylalanine and 2-naphthylacetic acid.

Disposition of detirelix, a potent luteinizing hormone-releasing hormone antagonist, in rats and monkeys.

The disposition of detirelix, a potent luteinizing hormone-releasing hormone (LHRH) antagonist, was studied in rats and monkeys. After a single 300-microgram/kg intravenous dose in rats, the plasma elimination t1/2 was 1.6 hr and the plasma clearance was 3.3 ml/min/kg. In the monkey, the mean t1/2 and plasma clearance were 7.1 hr and 1.3 ml/min/kg, respectively, after an 80-microgram/kg intravenous dose. Long plasma t1/2 values of 18.7 and 31.6 hr were observed after single 0.2- and 1.0-mg/kg subcutaneous doses in the monkey, suggesting the possibility of subcutaneous depot formation at the injection site. Biliary excretion was the predominant route of elimination of detirelix in both species. Less than 10% of the detirelix was excreted renally. A major metabolite, isolated from the rat bile, was the 1-4 tetrapeptide fragment of detirelix. This metabolite was formed by enzymatic hydrolysis of the Ser4-Tyr5 bond, one of the only two peptide bonds in detirelix not containing a D-amino acid.

Suppression of pituitary-gonadal function by a potent new luteinizing hormone-releasing hormone antagonist in normal men.

LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadal function by suppressing gonadotropin secretion. We studied the effects of a recently developed LHRH antagonist on the pituitary-gonadal axis in man. The antagonist Detirelix [( N-Ac-D-Nal(2)1, D-pCl-Phe2,D-Trp3, D-hArg(Et2)6, D-Ala10]LHRH) was given as a single sc injection to nine normal men at three dose levels (5, 10, and 20 mg) at intervals of at least 7 days. Serum FSH, LH, and testosterone levels were measured before treatment, at frequent intervals for 48 h, and 72, 96, and 168 h after administration of the antagonist. Mean serum FSH levels decreased (P less than 0.001) from 6.9 +/- 0.5 (+/- SEM) mIU/mL to nadirs of 4.4 +/- 1.1, 3.6 +/- 0.9, and 4.1 +/- 0.9 after the 5-, 10-, and 20-mg doses, respectively. Serum LH levels decreased (P less than 0.001) from 6.2 +/- 0.3 mIU/mL to nadirs of 3.3 +/- 0.4, 2.8 +/- 0.3, and 2.7 +/- 0.3 after all three doses. Serum testosterone levels decreased (P less than 0.001) in a dose-dependent fashion from 5.1 +/- 0.2 ng/mL to nadirs of 1.3 +/- 0.3, 0.9 +/- 0.3, and 0.6 +/- 0.1 after the same doses. After the initial testosterone decrease, however, escape occurred 12-28 h after the lower doses. The area under the response curve, describing hormone concentrations as a function of time during the study, diminished by 23 +/- 2%, 36 +/- 4%, and 36 +/- 3% for FSH, by 14 +/- 6%, 30% +/- 6%, and 34 +/- 5% for LH, and by 41 +/- 5%, 58 +/- 6%, and 68 +/- 4% for testosterone with the same doses, respectively. The apparent plasma disappearance half-life of Detirelix by RIA was at least 41 h after all three doses. Detirelix elicited only a minor local reaction; no systemic side-effects were observed within the dose range used. These results indicate that this LHRH antagonist is a safe, highly potent inhibitor of the human pituitary-gonadal axis with an exceptionally long duration of action.