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Pharmacokinetics of mifepristone after low oral doses

1996; Elsevier BV; Volume: 54; Issue: 4 Linguagem: Inglês

10.1016/s0010-7824(96)00193-x

1879-0518

Raimo Kekkonen, Oskari Heikinheimo, Erik Mandelin, Pekka Lähteenmäki,

Reproductive System and Pregnancy

Relatively low doses of the antiprogestin mifepristone (RU 486) have recently proven to be efficient for a variety of possible clinical uses of the drug. However, the pharmacokinetics after low single oral doses have not been characterized. We evaluated the pharmacokinetics of mifepristone following single ingestion of 2 and 25 mg in five women as well as repeated ingestion of 8 mg in two women. Maximal serum concentrations were reached rapidly (within 0.5-2 h) with all doses used. Serum mifepristone concentrations were proportional to the oral doses taken. The mean (+/- SD) areas under the concentration curves (AUCs) (0-24 h) were 1134 (+/- 144), 4846 (+/- 64), and 17,015 (+/- 4,421) h x ng/mL following 2, 8, and 25 mg doses, respectively. No cumulative increases in serum concentrations were detected with prolonged daily administration of 8 mg of mifepristone. The study subjects appeared to vary in their ability to metabolize mifepristone, as two different half-lives (t1/2) emerged after both 2 and 25 mg single doses (24.2 +/- 0.6 [SD] h for three subjects; and 44.4 +/- 1.8 [SD] h for two subjects). We conclude that within the dose range of 2-25 mg/day, the pharmacokinetics of mifepristone are linear, unlike those seen following ingestion of higher daily doses. Keeping in mind previously published data on the biological effects of low dose mifepristone administration, these data infer that certain effects of the drug, such as inhibition of ovulation, might be achieved at serum concentrations of approximately 100 ng/mL.At the outpatient clinic of Lohja District Hospital in Lohja, Finland, clinical researchers examined the pharmacokinetics of mifepristone in 5 healthy women, 29-37 years old, receiving a single dose of 2 mg mifepristone and of 25 mg mifepristone and in 2 other women receiving 8 mg mifepristone each day for 30 days. Regardless of the dose, serum concentrations of mifepristone peaked within 1.2-1.4 hours. These concentrations were proportional to the oral doses: 104-227 ng/ml after 2 mg dose; 474-561 ng/ml after 8 mg dose; and 1285-4851 ng/ml after 25 mg dose. The areas under the concentration curves (0-24 hours) were also proportional to the oral doses: 1134.4, 4846, and 17,015.2, respectively. Daily doses of 8 mg mifepristone over 30 days did not effect cumulative increases in serum concentrations. The women taking the 2 mg and 25 mg single oral doses exhibited different half-lives (24.2 [3 women] vs. 44.4 [2 women] hours; p = 0.001), suggesting that they varied in their ability to metabolize mifepristone. These findings show that, at daily ingestion of 2-25 mg mifepristone, the pharmacokinetics of mifepristone are linear. Based on these findings, the authors think that inhibition of ovulation might be achieved at serum concentrations of about 100 ng/ml.