Absorption And Plasma Concentration

The Pharmacokinetics of mifepristone and its metabolites are not linear. Following oral administration of single doses of mifepristone 100, 400, 600 and 800mg to healthy female volunteers maximum plasma concentrations were about 2.5mg/L and differed between the 200 and 800mg doses only 2 hours after ingestion╣ (Heikinheimo et al. 1986; Lahteenmaki et al. 1987), although Nagoshi et al. (1991) reported maximum concentrations of 1.5 and 3.3 mg/L after single doses of 200 and 400mg, respectively. After a single 600mg dose maximum plasma concentration was about 2mg/L at 1.35 hours. High doses of 10 and 25 mg/Kg in healthy female and male volunteers produced maximum plasma concentrations of progesterone receptor - reactive material of 5.17 to 7.5mg/L▓ (Kawai et al. 1987). Maximum plasma concentration were obtained 0.7 to 1.5 hours after oral administration. The parent drug and its metabolites (using HPLC) were still detectable 6 to 7 days after a single dose│ (Nagoshi et al. 1991) and for 10 days using radioimmunoassay¬ (Lahteenmaki et al. 1987).

Administration of 12.5, 25, 50, or 100mg twice daily for 4 days to healthy female volunteers resulted in similar plasma concentrations of 1.4 to 1.7 mg/L at dosages >50mg twice daily (Heikinheimo et al. 1989) and it was suggested that the lack of increase in plasma drug concentration when dosage increased above 50mg twice daily is partly explained by saturation of &-1-acid glycoprotein (AAG), the serum binding protein for mifepristone in man (Heikinheimo et al. 1987 a), which has a binding capacity lower than the therapeutic doses.

During chromic administration of mifepristone 10 to 20mg/Kg to patients with Cushing's Syndrome, plasma concentrations were relatively constant at 5.06 to 11.8mg/L when measured by radioreceptor assay (Kawai et al. 1987). Absolute bioavailibility after a dose of 20mg is 69%.