title: Circulating concentrations of the antiprogestins CDB-2914 and mifepristone in the female rhesus monkey following various routes of administration.
abstract: The overall aim of these studies was to investigate the oral and i.m. bioavailability of CDB-2914 in intact female rhesus monkeys, and to compare the serum concentrations of CDB-2914 with that of mifepristone following oral administration. In the first study, a 50 mg bolus of CDB-2914 per monkey was administered intravenously, orally or intramuscularly. The area under the serum concentration-time curve for 72 h (AUC(0-72)) following i.v. injection was 18 320 +/- 2718 ng/ml*h, and that for oral administration was 10 464 +/- 3248 ng/ml*h. Thus, the oral bioavailability of CDB-2914 equivalents was 56%. The AUC(0-168 h) following i.m. injection was 11 226 +/- 1130 ng/ml*h. Therefore, the i.m. bioavailability of CDB-2914 equivalents was 62%. In the second study, the serum concentrations of CDB-2914 and mifepristone equivalents were compared following an oral bolus dose in two different formulations. When administered at 5 mg/kg in aqueous suspending vehicle (ASV), the mean peak serum concentration (C(max)) of CDB-2914 equivalents (192 +/- 64 ng/ml) occurred at 5 +/- 1 h, whereas the C(max) of mifepristone equivalents (82 +/- 25 ng/ml) occurred at 3 +/- 1 h. Following administration in gelatin capsules (35 mg/monkey), the C(max) of CDB-2914 equivalents (129 +/- 24 ng/ml) occurred at 5 +/- 1 h, while the C(max) of mifepristone equivalents (31 +/- 8 ng/ml) occurred at 3 +/- 1 h. The serum concentration (AUC(0-120 h)) of CDB-2914 equivalents was 4.7- or 5. 3-fold greater than that of mifepristone equivalents when administered orally in ASV or gelatin capsules respectively. The serum protein binding characteristics of CDB-2914 were also studied. CDB-2914 bound to human alpha(1)-acid glycoprotein (AAG), but not with as high an affinity as mifepristone. In contrast, neither CDB-2914 nor mifepristone bound with high affinity to AAG, corticosteroid binding globulin or sex hormone binding globulin in monkey serum. Collectively, these results indicated that CDB-2914 was more efficiently absorbed than mifepristone following oral administration to female rhesus monkeys.
authors.affiliation: BIOQUAL, Inc., Rockville, MD, 20850, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Larner
authors.forename: J R
authors.initials: JR
authors.lastname: Reel
authors.forename: R P
authors.initials: RP
authors.lastname: Blye
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D003283:Contraceptives, Postcoital, Synthetic / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D004304:Dosage Forms; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008253:Macaca mulatta; D015735:Mifepristone / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D009649:Norpregnadienes / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D014156:Transcortin / Q000378:metabolism
chemical_list: D003283:Contraceptives, Postcoital, Synthetic; D004304:Dosage Forms; D009649:Norpregnadienes; D012738:Sex Hormone-Binding Globulin; D015735:Mifepristone; C094854:ulipristal; D014156:Transcortin