Distribution, metabolism and excretion of a synthetic androgen 7alpha-methyl-19-nortestosterone, a potential male-contraceptive.
A synthetic androgen 7alpha-Methyl-19-nortestosterone (MENT) has a potential for therapeutic use in 'androgen replacement therapy' for hypogonadal men or as a hormonal male-contraceptive in normal men. Its tissue distribution, excretion and metabolic enzyme(s) have not been reported. Therefore, the present study tested the distribution and excretion of MENT in Sprague-Dawley rats castrated 24h prior to the injection of tritium-labeled MENT ((3)H-MENT). Rats were euthanized at different time intervals after dosing, and the amount of radioactivity in various tissues/organs was measured following combustion in a Packard oxidizer. The radioactivity (% injected dose) was highest in the duodenal contents in the first 30min of injection. Specific uptake of the steroid was observed in target tissues such as ventral prostate and seminal vesicles at 6h, while in other tissues radioactivity equilibrated with blood. Liver and duodenum maintained high radioactivity throughout, as these organs were actively involved in the metabolism and excretion of most drugs. The excretion of (3)H-MENT was investigated after subcutaneous injection of (3)H-MENT into male rats housed in metabolic cages. Urine and feces were collected at different time intervals (up to 72h) following injection. Results showed that the radioactivity was excreted via feces and urine in equal amounts by 30h. Aiming to identify enzyme(s) involved in the MENT metabolism, we performed in vitro metabolism of (3)H-MENT using rat and human liver microsomes, cytosol and recombinant cytochrome P(450) (CYP) isozymes. The metabolites were separated by thin-layer chromatography (TLC). Three putative metabolites (in accordance with the report of Agarwal and Monder [Agarwal AK, Monder C. In vitro metabolism of 7alpha-methyl-19-nortestosterone by rat liver, prostate, and epididymis. Endocrinology 1988;123:2187-93]), [i] 3-hydroxylated MENT by both rat and human liver cytosol; [ii] 16alpha-hydroxylated MENT (a polar metabolite) by both rat and human hepatic microsomes; and [iii] 7alpha-methyl-19-norandrostenedione (a non-polar metabolite) by human hepatic microsomes, were obtained. By employing chemical inhibitors and specific anti-CYP antibodies, (3)H-MENT was found to be metabolized specifically by rat CYP 2C11 and 3-hydroxysteroid dehydrogenase (3-HSD) enzymes whereas in humans it was accomplished by CYP 3A4, 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 3-HSD enzymes.
Prasad
Pramod Vishwanath
PV
Center for Biomedical Research, The Population Council, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. pkumar@popcouncil.org
Arumugam
Ramamani
R
Willman
Mark
M
Ge
Ren-Shan
RS
Sitruk-Ware
Regine
R
Kumar
Narender
N
D000818:Animals; D003272:Contraceptive Agents, Male / Q000493:pharmacokinetics*; D003282:Contraceptives, Postcoital, Hormonal / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley
D003272:Contraceptive Agents, Male; D003282:Contraceptives, Postcoital, Hormonal; C064709:trestolone; D009277:Nandrolone