Mifepristone: bioavailability, pharmacokinetics and use-effectiveness.
The potentiality of mifepristone as an abortifacient and contraceptive drug along with its pharmacokinetic parameters is reviewed. Mifepristone or RU486 acts as antagonist to progestational and glucocorticoid functions. It is an orally active compound with nearly 70% absorption rate but its bioavailability is reduced to around 40% because of the first-pass effect. Peak plasma concentrations of 1.9 +/- 0.8, 3.8 +/- 0.9 and 5.3 +/- 1.3 micromol/l are reached within 1-2 h after oral administration of 50, 200 and 600 mg mifepristone in women, respectively, and are maintained at relatively high level up to 48 or 72 h depending on the ingested dose. The plasma kinetics of mifepristone followed two-compartment open model with a mean alpha-half-life of 1.4h, volume of distribution 1.47 l/kg and beta-half-life of 20-30 h in most of the subjects studied. Clearance from the body was mainly through feces (83%). Biologically active mono-demethylated, di-demethylated and hydroxylated metabolites were found in plasma soon after oral administration of mifepristone. RU486 and its mono-demethylated metabolite bind to progesterone receptors with high affinity. Mifepristone-bound receptor dimers suppress transcription activation and thus, bring about anti-progestational activity that makes mifepristone a potential abortifacient and contraceptive agent. Clinical trials for termination of early pregnancy with 50-600 mg mifepristone plus a prostaglandin analogue achieved a success rate of 82-97%. However, abdominal pain, cramping, nausea, vomiting, bleeding and delay in onset of the next menstrual cycle were the side effects. Administration of 25 mg mifepristone twice 12h apart, as a post-coital contraceptive showed 100% contraceptive efficacy. A low dose of mifepristone which does not inhibit ovulation reduced fertility significantly by affecting endometrial milieu. These findings suggest that reduced dose(s) of mifepristone, 200 mg or less, may be used as a post-coital contraceptive and in combination with vaginal misoprostol for termination of early pregnancy with high efficacy and minimal or no side effects.
Sarkar
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Department of Reproductive Biology, All India Institute of Medical Sciences, Ansarinagar, 110029, New Delhi, India.
D000021:Abortifacient Agents, Steroidal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D003283:Contraceptives, Postcoital, Synthetic / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D015735:Mifepristone / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D000021:Abortifacient Agents, Steroidal; D003283:Contraceptives, Postcoital, Synthetic; D015735:Mifepristone