Pharmacokinetics, tissue distribution, and excretion of nomegestrol acetate in female rats.

Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-norprogesterone, is an orally active drug with a strong affinity for the progesterone receptor. NOMAC inhibits ovulation and is devoid of undesirable androgenic and estrogenic activities. The aim of this study was to evaluate the pharmacokinetics, tissue distribution, and excretion of NOMAC in female rats. Sprague-Dawley female rats were orally administered a single dose of NOMAC (10, 20 or 40 mg/kg) and drug plasma concentrations at different times were determined by RP-HPLC. Tissue distribution at 1, 2, and 4 h and excretion of NOMAC into bile, urine, and feces after dosing were investigated. The results showed that NOMAC was rapidly absorbed after oral administration, with [Formula: see text] of 1-2 h. The plasma concentration-time curves were fitted in a two-compartment model. The exposure to NOMAC ([Formula: see text] and [Formula: see text]) increased dose proportionally from 10 to 40 mg/kg. The average CL and [Formula: see text] were 5.58 L/(h·kg) and 10.8 h, respectively. The highest concentrations of NOMAC in ovary, liver, kidney, lung, heart, brain, spleen, muscle, and uterus were observed at 2 h, whereas the highest concentrations in stomach, pituitary, and hypothalamus appeared at 1 h. The total cumulative excretion of NOMAC in feces (0-72 h), urine (0-72 h), and bile (0-48 h) was ~1.06, 0.03, and 0.08 % of the oral administered dose, respectively. This study indicated that NOMAC had a widespread distribution in tissues, including ovary, pituitary, and hypothalamus, which are main target tissues where NOMAC inhibits ovulation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation was found in the drug elimination; however, it did not significantly affect [Formula: see text].

A four-year evaluation of the chronic toxicity of megestrol acetate in dogs.

PIP: A 4-year evaluation of the chronic toxicity of megestrol acetate in dogs is reported. .01, .1 or .25 mg of megestrol acetate/kg/day or .25 mg of chlormadinone acetate/kg/day was administered orally for 4 years t o female beagle dogs. The hormone-treated dogs tended to gain more weig ht than did the controls (controls vs. .25 mg megestrol acetate every month after the 3rd p less than .01). All treated dogs revealed decreased evidence of estrus. Mucoid vaginal discharges were more prevalent among the middle and high dose groups. Mean hemoglobin, packed cell volume and total erythrocyte values were slightly decreased while mean total leucocyte count and erythrocyte sedimentation rates were slightly increased in the middle and high dose groups. Clotting me chanism did not reveal any disturbances. Evidence of diabetes consistin g of bilateral cataracts, elevated serum glucose concentrations and glycosuria after 4 years in 2 of 16 high-dose megestrol acetate and in 6 of 15 chlormadinone acetate-treated dogs was revealed. It is concluded that the effects of megestrol acetate were similar but less severe than those of chlormadinone acetate.^ieng