Pharmacokinetics and pharmacodynamics of anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate)

In order to determine the pharmacokinetics of anordrin a dose of 0.2 mg/kg of [3-¹⁴C]anordrin was administered i.v. to 5 cynomolgus monkeys; the same monkeys received the same dose i.m. at a later date. An additional 3 monkeys received 1.0 mg/kg of [3-¹⁴C]anordrin i.m. After administration of the compound, the dipropionate esters of anordrin were rapidly hydrolyzed to the dihydroxy parent compound, anordiol. After i.v. administration, anordrin had a mean residence time (MRT) of 5.0 ± 1.3 (SE) min. [¹⁴C]Anordiol formed from [¹⁴C]anordrin had an MRT of 139 ± 27 (SE) min. The metabolic clearance rates (MCR) of anordrin and anordiol were 55 and 34 mL/min·kg, respectively. The apparent volume of distribution at steady state (V_ss) for anordrin was 276 mL/kg, 7.5% of body weight of the animals; anordiol had a much larger V_ss of 4460 mL/kg. The MRT of anordiol after i.m. administration of 1.0 mg/kg of [¹⁴C]anordrin was 26.3 days. An average of 44% of the dose appeared in urine regardless of the route of administration or dose. The MRT values of total radioactivity were the same when calculated from serum or urine after an i.v. dose, but after i.m. administration, values from urine were approximately 60% of that calculated from serum, indicating that products appearing in urine had a shorter MRT than products appearing primarily in feces. A separate group of monkeys was given anordrin i.m. in doses ranging from 0.1 to 0.4 mg/kg on the first day of menses The regression of length of menstrual cycle on dose was significant (P = 0.004). Control cycle length was 30 days and the response was linear to 76 days with the maximum dose given.