Tissue distribution and pharmacokinetics of centchroman. A new nonsteroidal postcoital contraceptive agent and its 7-desmethyl metabolite in female rats after a single oral dose.

This study reports assay methodology, tissue distribution, and the basic pharmacokinetic behavior of centchroman and its 7-desmethyl metabolite [7-desmethyl centchroman (DMC)] after a single 12.5 mg/kg po dose in young female rats. Plasma, liver, lung, spleen, uterus, and adipose tissue were collected at various time intervals up to 14 days after dose. Reversed-phase HPLC, coupled with fluorescence detector, was used for simultaneous determination of centchroman and DMC in biosamples. The drug and metabolite were quantitated up to 2 and 5 ng/ml in plasma and 10 and 20 ng/g in tissues, respectively. The assay method was validated in terms of accuracy, precision, interassay, and intraassay variability, and was found to be reliable and reproducible. Peak centchroman levels in all of the tissues were found between 8-12 hr, whereas DMC peaks appeared between 8 and 24 hr, except that in liver the first peak of 1.2 micrograms/g appeared in the 1-hr sample. Tissue-to-plasma concentration ratios of centchroman were > 200 times in the lung; > 100 times in the spleen, liver, and adipose tissue; and > 40 times in the uterus at maxima in each tissue. Similarly, tissue concentrations of DMC were > 350 times in the lung, > 100 times in the liver and spleen, and > 25 times in the uterus and adipose tissue than in the plasma. High tissue-to-plasma concentration ratios of metabolites than the parent drug are indicative of its greater affinity for tissues. Terminal half-life of the centchroman and DMC in plasma were 24.1 and 36.6 hr, respectively. The mean residence time of centchroman was highest in the liver (78.4 hr), followed by the uterus (72.7 hr), adipose tissue (47.5 hr), lung (46 hr), spleen (44.1 hr), and plasma (37.7 hr). The mean residence time of DMC was also highest in the liver (133.7 hr), followed by the uterus (122 hr), adipose tissue (85.2 hr), lung (62.6 hr), spleen (62.6 hr), and plasma (48.2 hr).

Antiprogestins: mechanism of action and contraceptive potential.

Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.

PIP: Antiprogestins have a 17-alpha substitution, which promotes higher binding affinity to both progesterone and glucocorticoid receptors, and an 11-beta substitution, which appears to be responsible for the antagonistic action. Antiprogestins also exhibit progestin agonistic and even antiestrogenic properties. Induction of a medical abortion in very early pregnancy is the most frequent clinical use of the antiprogestin mifepristone (RU-486). Antiprogestins may someday be used as a contraceptive since very low doses of antiprogestins cause considerable changes in endometrial morphology. At these low doses, they do not affect hormonal secretion or ovulation or bleeding patterns. At high doses, they delay ovulation but are associated with unopposed estrogen action on the endometrium. At low doses, antiprogestins do not always delay ovulation. RU-486 is a very effective and safe postcoital contraceptive. Antiprogestins may be beneficial in treating endometriosis, uterine myoma, and steroid-dependent tumors (e.g., breast cancer). They may be used to induce labor in cases of intrauterine fetal death. Antiprogestins may prove useful in treating Cushing's syndrome due to ectopic adrenocorticotropic hormone secretion, in lowering intraocular pressure in glaucoma, and in preventing the progression of viral diseases in humans. They also appear to have even more potential benefits, such as treatment of burns.

A new class of non-hormonal contragestational agents: pharmacodynamic-pharmacokinetic relationships.

PIP: As part of a research program designed to find new potential antifertility agents, new non-hormonal, non-prostaglandin-like compounds belonging to the class of 2-phenyl-triazole (5,1-a) isoindoles Ia and the corresponding dehydro-isoquinolines Ib were identified in the laboratories of the Departments of Pharmacokinetics, Organic Chemsitry, and Endocrinology (Gruppo Lepetit, Milan, Italy). These new structures were shown to be effective at nontoxic doses in several animal species as post-implantation, early pregnancy termination agents. Starting from these leader compounds, studies designed to clarify simultaneously both their spectrum of activity and the structure-activity relationships were undertaken. Following this initial explorative phase, keeping in mind that an antifertility agent must be highly effective over a period of time sufficiently long to block a dynamic process such as pregnancy, selected compounds were studied in depth in order to determine the relationships between their bioavailability and their effectiveness. This manuscript reviews the multidisciplinary research which led to the selection of the 1st generation compounds that have not only the very high potencies but also the diverse kinetic characteristics to make them suitable for potential use in animals and in humans. In the development of these new contragestational agents, it was apparent early that the achievement of the biological effect would be strictly dependent upon prolonged availability. Thus, in the primary screening, the period of treatment in pregnancy (most effective time), the route (subcutaneous), and the schedule of treatment (multiple daily doses) chosen, were those least affected by kinetic and metabolic factors. Structure-activity relationships studies in 2 species with marked differences in sensitivity (rat, hamster) made it possible to ascertain the key portions of the molecules and the types of substituents that could either improve the activity or reduce the species specificity. This initial research phase led to the selection of several compounds with high pregnancy terminating activity after multiple parenteral administration. Concurrently, the contragestational activity of some of the most interesting products, possessing different physico-chemical properties, was measured at various stages of gestation, when given in different schedules, by different routes, and in different vehicles. The main evidence that emerged, when related to the pharmacokinetic profiles and the phyisico-chemical properties of each molecule, indicated the following kinetic-activity relationships: the effectiveness of the compounds was shown to be dependent on time of gestation, route, vehicle, and schedule of administration; the ideal time course of the compounds at the site of action requires sustained kinetics, while short exposures even to high concentrations are not very effective in interrupting the embryonic development; the maximal effectiveness can be obtained when the exposure of the products of conception to the drug action lasts for whole length of time needed to arrest pregnancy; the period of efficacy during pregnancy can be lengthened by administering long lasting compounds before the period of maximal effectiveness; and the loss of contragestational activity observed when the compounds are given orally is mainly due to a metabolic first-pass.^ieng

[Postcoital contraception in primates. II. Examination of STS 153 and STS 287 as interceptives in the baboon (Papio hamadryas)]. / Postkoitale Kontrazeption bei Primaten. II. Prüfung von STS 153 und STS 287 als Interzeptiva beim Pavian (Papio hamadryas).

The interceptive activity of 2 new synthesized steroid compounds: STS 153 (17 beta-Phenylaminocarbonyloxy-estra-1,3,5(10)-triene-3-methyl ether and STS 287 (16 alpha-Bromo-17 beta-[N',N'-dimethylhydrazino]-carbonyloxy-estra-1,3,5(10)-triene-3-methyl ether) and of 17 alpha-Ethynylestradiol was investigated in baboons.--Postcoital oral administration of 1--3 mg/kg b. w. STS 153 for 5--7 days and of 1 mg/kg b. w. STS 287 for 5 days resulted in a fertility inhibition of about 90% and 95% respectively. A dose of 2 mg/kg b. w. of ethynylestradiol was necessary to attain complete fertility inhibition. Following administration of STS 153 and STS 287, side effects were not observed. Pharmacokinetic aspects are discussed.

17alpha-Ethyl-20alpha-and -20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents.

The 17alpha-ethyl-substituted analogs of the two epimeric 20-dihydroprogesterones, allopregnadedione and pregn-5-ene-3,20-dione, were synthesized and evaluated for their possible oral contragestational (postcoital antifertility) activity in the rat. The compounds, though bound strongly to the progesterone receptor in vitro, were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.

PIP: 17alpha-20alpha- and 20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents were investigated in the rat, and the syntheses of 17 alpha-ethyl-substituted analogs of the 2 epimeric 20-dihydroprogesterones, allopregnanedione and pregn-5-ene-3,20 dione are presented. The compounds were administered orally to 5 rats on Days 1-6 of gestation for studies related to effects on implantation or on Days 9-12 of gestation for studies related to drug effects on pregnancy after implantation. Postmortem examination was carried out between Day 14 and Day 21 of gestation. The compounds were strongly bound to the pr ogesterone receptor in vitro but were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.