Jean Salmon

Pharmacokinetics of RU 486

The pharmacokinetics of RU 486 have been studied in man, rats and cynomolgus monkeys. Single pharmacological doses were given (from 1.3 mg/kg−1 in man (oral) to 3−5 mg/kg−1 in animal species), using a tritiated compound. Radiometric assay and, in some cases, RIA were used. Absorption was satisfactory in all species, but the compound underwent a presystemic effect that reduced its bioavailability to 40% in man and rats and 15% in monkeys. Extravascular diffusion was much greater in animal species than in man; the apparent initial volume of distribution was equivalent to the body weight in rats and twice the body weight in monkeys. However, it accounted for only 10% of the body weight in man.

Pharmacokinetics and metabolism of moxestrol in animals—rat, dog and monkey

The pharmacokinetics and metabolism of moxestrol have been compared in the rat, dog and monkey (rhesus and baboon) and, in some instances, confronted with data simultaneously obtained for ethynl estradiol and previously obtained in humans. The apparent initial volume of distribution (AIVD) of total radioactivity after i.v. administration was of the order of body volume in all species under study; the AIVD of intact moxestrol was even higher. This is in agreement with moxestrols low binding to specific and non-specific plasma proteins. The half-life of total radioactivity elimination was 14-18 h in the rat and rhesus monkey, but longer (43 and 78 h, i.v. and oral respectively) in the baboon. In the dog, the elimination phase could not be distinguished from the distribution phase and had a half-life of 2 h. The half-life of unchanged moxestrol elimination was shorter and very similar in the rhesus, baboon and human (6.6, 7.5 and 8.2 h respectively) and only 1.4 h in the dog. Regardless of the route of administration or the species under study, the clearance and elimination rate of unchanged moxestrol were higher than of total radioactivity implying that metabolites and/or conjugation products were eliminated more slowly than intact product from plasma. Orally administered moxestrol was rapidly absorbed in all species. Since clearance of total radioactivity and of moxestrol was faster after i.v. than oral administration, but the radioactivity levels excreted in the urine were identical for the two routes, a significant first-pass-effect probably occurred in the liver. Radioactivity distribution in tissues was examined in the rat. Total radioactivity was higher 24 h after administration of labelled moxestrol than of labelled ethynyl estradiol in endocrine tissues; it was equivalent or less in the other tissues. For all tissues, the elimination rate of moxestrol was greater than, or equal to, that of ethynyl estradiol. In dog urine, the only product identified was moxestrol; in rhesus or baboon monkey urine, the principal metabolites were catechol estrogens, which were also present in appreciable amount in rat bile (as methyl ethers) but were minor metabolites in human urine. Hydroxylation in position 16 occurred in rats and humans only, in position 15 alpha in humans and, to a much lesser extent, in rats and monkeys. Thus, the metabolic profile of moxestrol in rats most closely resembles that in humans.

Novel radioactive estradienes labelled with iodine

Novel radioactive estradienes labelled with iodine of the formula ##STR1## in the form of their syn or anti isomers or mixtures thereof wherein the wavy line indicates anti or syn position, R is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and acyl of an organic carboxylic acid of 1 to 12 carbon atoms and R1 is the residue of an amino acid R1 NH2 possessing an iodine acceptor group or a derivative thereof labelled with iodine 125 or 131 and their preparation and novel intermediates, antigens prepared from the compounds of formula I and bovine seric albumin or human seric albumin and their preparation and their use for the preparation of antibodies.

Reference compounds for the study op moxestrol metabolism

Reference compounds for the subsequent identification of the metabolites of the potent estrogen, moxestrol (R 2858) , in various species were isolated from the bile of phenobarbital pretreated rats or obtained via enzymatic hydroxylation by microorganisms. A few of them were prepared by chemical synthesis. The structures of all these compounds were determined by physical and chemical methods.

Novel radioactive estradienes

Novel radioactive estradienes labelled with tritium of the formula ##STR1## wherein 3 H is tritium and R is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and acyl of an organic carboxylic acid of 1 to 10 carbon atoms and the study and radioimmunological determination of non-radioactive 11β-(4-dimethylaminophenyl)-17α-(prop-1-ynyl)-Δ4,9 -estradiene-17β-ol-3-one and its metabolites in biological fluids and novel intermediates.

Novel radioactive estratrienes

Novel radioactive DELTA 4,9,11-estratrienes marked with iodine 125 or 131 having the formula I wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and acyl of an organic carboxylic acid of 2 to 12 carbon atoms, R1 is the reminder of an amino acid of the formula R1NH2 or a derivative thereof being marked with iodine 125 or 131 and the wavy lines indicate the -OR is in the alpha - or beta -position and the oximido group is in the syn or anti position, a process and intermediates for their preparation, antigens prepared therefrom and use thereof to prepare antibodies.