PHARMACOKINETICS OF 7-ALPHA-METHYL-19-NORTESTOSTERONE IN MEN AND CYNOMOLGUS MONKEYS

Testosterone and its esters are widely used for androgen replacement t herapy. In the prostate, testosterone is 5 alpha-reduced to dihydrotes tosterone (DHT), which leads to an amplification of its stimulatory ac tivity in this and other tissues that have significant 5 alpha-reducta se activity. While this amplification is essential during fetal develo pment, it has potentially undesirable consequences during adult life. 7 alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androge n that does not undergo 5 alpha reduction and is therefore being inves tigated for long-term clinical use because it is expected to be less s timulatory to the prostate. Since we anticipate using MENT acetate (ME NT Ac) rather than MENT as the form of this androgen in humans, the bi oavailability of MENT following the administration of MENT and MENT Ac was investigated in cynomolgus monkeys. Equimolar concentrations of M ENT or MENT Ac were administered as a continuous subcutaneous infusion via Alzet osmotic pumps. Serum MENT levels were measured by radioimmu noassay (RIA) in blood samples collected daily for 4 days during stead y state. The serum MENT levels were not significantly different in the two groups (11.3 +/- 1.6 vs. 13.1 +/- 1.2 nmol/L). This suggested tha t MENT Ac was rapidly converted to MENT in circulation. The hydrolysis of MENT Ac to MENT was confirmed by the in vitro incubation of MENT A c with blood or plasma and the demonstration of MENT in products follo wing separation by high-performance liquid chromatography (HPLC). Foll owing the demonstration of the safety of MENT Ac in subchronic toxicit y studies in rats and rabbits, a pharmacokinetic study was performed i n men. In normal men, a single intravenous bolus of 500 mu g of MENT l ed to peak serum MENT levels at 3 minutes after dosing (when the first samples were collected), followed by an exponential decline, reaching undetectable levels by 180 minutes. The average terminal half-life an d the metabolic clearance rate (MCR) were calculated to be 40 minutes and 2,360 L/day, respectively. The results of the pharmacokinetic stud ies show that in both men and monkeys, the MCR of MENT is much faster than the values reported for testosterone. The faster MCR can be attri buted, in part, to the finding that, in contrast to testosterone, MENT showed no binding to sex hormone binding globulin (SHBG).