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.

In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone

“…The longer apparent t 1/2 obtained by RIA or RRA is likely due to cross-reactivity with various metabolites. As described previously [26], monoclonal antibodies to mifepristone provided by Dr. Fortune Kohen (Weitzman Institute of Science, Rehovot, Israel) exhibited 86, 57, and <1% cross-reactivity with monodemethylated, didemethylated, and hydroxylated mifepristone, respectively. By analogy to the authenticated pathway for metabolism of mifepristone, putative metabolites have been proposed for CDB-2914 and CDB-4124 involving monodemethylation, didemethylation, and hydroxylation at the 17␣ position.…”

“…By analogy to the authenticated pathway for metabolism of mifepristone, putative metabolites have been proposed for CDB-2914 and CDB-4124 involving monodemethylation, didemethylation, and hydroxylation at the 17␣ position. We have developed an RIA for CDB-2914 [26] which employs rabbit polyclonal antibodies. This antiserum cross reacts extensively with several of the putative metabolites/synthetic derivatives of CDB-2914 (monodemethylated, 90%; didemethylated, 62%; aromatic A-ring, 25%; 17␣-hydroxy, <1%).…”

Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development

“…Peak serum concentrations are achieved in 1 --2 h. Its half-life is 25 --30 h. It has three important metabolites --mono-and di-methylated and hydroxylated forms --the first and third of which also bind to the progestin receptor. Elimination is prolonged due to enterohepatic recirculation of mifepristone and its metabolites following oral administration and to the fact that adipose tissue also provides a potential reservoir for mifepristone and its metabolites [58].…”

“…However, UPA can be taken on an empty stomach or with food. In circulation, 94% of UPA is bound to plasma proteins, such as albumin, high density lipoprotein, and alpha-1-acid glycoprotein, but UPA binds with less affinity than mifepristone [58]. The terminal half-life of UPA in plasma following the single 30 mg dose is 32.4 ± 0.3 h. It is hepatically metabolized primarily by the cytochrome p450 3A4 (CYP3A4) enzyme system [56].…”

Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors

“…Whereas RU486, in association with prostaglandins, is used solely for medical termination of pregnancy, UPA has a broad range of therapeutic applications including emergency contraception and the preoperative treatment of uterine fibroids [10]. It has been proposed that UPA has greater bioavailability than RU486 [11]. Moreover, UPA has been shown to be more efficient than RU486 when administered per os.…”