lilopristone and Endometriosis

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an "abortion pill," antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (alpha 1-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t1/2 than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytes in primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and never antiprogestational agents.

Topics: Abortifacient Agents; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Contraceptives, Postcoital, Synthetic; Endometriosis; Estrenes; Female; Gonanes; Hormone Antagonists; Humans; Mifepristone; Progestins

Antiprogestogens, which block the action of progesterone at the cellular level through binding to the progesterone receptor, are proving to be one of the most significant developments in endocrinology in recent years. Several hundreds of such compounds have been synthesized, but only a few of them have been evaluated to any significant extent in biological screening models and, to our knowledge, only three compounds, namely mifepristone, lilopristone (ZK 98.734) and onapristone (ZK 98.299) have been given to humans. Most of the clinical research to date has focused on the use of mifepristone given in combination with prostaglandin for termination of early pregnancy, an indication for which the compound is being used routinely in four countries so far, i.e. China, France, the UK and Sweden. The gynaecological and obstetrical applications in which antiprogestogens have been shown to be of value to date include ripening of the pregnant cervix prior to pregnancy termination, sensitization of the uterus to prostaglandins in second-trimester abortion, and induction of labour. Available data suggest that antiprogestogens have no place in the conservative treatment of ectopic pregnancy or in the treatment of premenstrual tension. In fertility regulation, the sequential combination regimen of mifepristone plus prostaglandin as used for inducing abortion has proved to be effective also for menses induction and can be expected to be an efficacious once-a-month contraceptive. Mifepristone alone, without adjuvant prostaglandin, has yielded promising results as an anti-implantation agent and in emergency contraception. Other potential uses include once-a-week contraception, ovulation inhibition (in a sequential regimen with a progestogen), and as a daily mini-pill. Mifepristone, and other antiprogestogens for which biological data have been reported also bind to the cellular receptors for glucocorticoid hormones and, consequently, possess antiglucocorticoid in addition to their antiprogestational activity. Because of this antiglucocorticoid effect, mifepristone has been employed successfully in the palliative treatment of hypercortisolism due to Cushing's syndrome, and its use has been proposed for treating certain forms of depression and of glaucoma, and in wound healing. However, for scientific and practical reasons, it would be preferable if molecules were developed that have only the antiprogestational or the antiglucocorticoid activity rather than both.

Topics: Abortion, Induced; Antineoplastic Agents; Breast Neoplasms; Contraception; Contraceptives, Oral, Synthetic; Endometrial Neoplasms; Endometriosis; Estrenes; Female; Gonanes; Humans; Labor, Induced; Mifepristone; Pregnancy; Pregnancy Trimester, Second; Progestins; Prostaglandins; Receptors, Progesterone

To evaluate the effects of antiprogestins mifepristone and lilopristone on proliferation and expressions of nuclear factor-kappa B (NF-kappaB) of ectopic stromal cells in vitro.. The ectopic stromal cells of ovary were cultured in vitro. Methyl thiazolyl tetrazolium method was used to evaluate proliferative activity of ectopic stromal cells. Cells were divided into five groups according to drug concentration: control group, group I and group II of mifepristone and of lilopristone. The expressions of NF-kappaB P65 and NF-kappaB P65 mRNA of ectopic stromal cells were determined by immunocytochemistry and in situ hybridization of cell slice.. Antiprogestins mifepristone and lilopristone were able to significantly suppress the proliferation of ectopic stromal cells in a time- and dose-dependent manner in vitro. The expressions of NF-kappaB P65 and NF-kappaB P65 mRNA of ectopic stromal cells in the control group were higher than that of group I and group II. Their expressions in mifepristone groups were higher than that of lilopristone groups.. Antiprogestin mifepristone and lilopristone could significantly suppress the proliferation of ectopic stromal cells in a time- and dose-dependent manner in vitro. The action mechanisms may be associated with the suppression of expression of NF-kappaB P65 mRNA and NF-kappaB P65.

Topics: Adult; Cell Proliferation; Cells, Cultured; Endometriosis; Endometrium; Estrenes; Female; Hormone Antagonists; Humans; Mifepristone; RNA, Messenger; Stromal Cells; Transcription Factor RelA