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Pharmacokinetics, Tissue Distribution, and Excretion of Nomegestrol Acetate in Female Rats

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Pharmacokinetics, Tissue Distribution, and Excretion of Nomegestrol Acetate in Female Rats Eur J Drug Metab Pharmacokinet (2015) 40:435–442 DOI 10.1007/s13318-014-0224-7 ORIGINAL PAPER Pharmacokinetics, tissue distribution, and excretion of nomegestrol acetate in female rats Qingbiao Huang • Xiaoke Chen • Yan Zhu • Lin Cao • Jim E. Riviere Received: 16 May 2014 / Accepted: 20 August 2014 / Published online: 29 August 2014 Ó Springer International Publishing Switzerland 2014 Abstract Nomegestrol acetate (NOMAC), a synthetic 1–2 h. The plasma concentration–time curves were fitted in progestogen derived from 19-norprogesterone, is an orally a two-compartment model. The exposure to NOMAC (Cmax active drug with a strong affinity for the progesterone and AUC) increased dose proportionally from 10 to 40 mg/ receptor. NOMAC inhibits ovulation and is devoid of kg. The average CL and t1=2b were 5.58 L/(hÁkg) and 10.8 h, undesirable androgenic and estrogenic activities. The aim respectively. The highest concentrations of NOMAC in of this study was to evaluate the pharmacokinetics, tissue ovary, liver, kidney, lung, heart, brain, spleen, muscle, and distribution, and excretion of NOMAC in female rats. uterus were observed at 2 h, whereas the highest concen- Sprague–Dawley female rats were orally administered a trations in stomach, pituitary, and hypothalamus appeared at single dose of NOMAC (10, 20 or 40 mg/kg) and drug 1 h. The total cumulative excretion of NOMAC in feces plasma concentrations at different times were determined (0–72 h), urine (0–72 h), and bile (0–48 h) was *1.06, 0.03, by RP-HPLC. Tissue distribution at 1, 2, and 4 h and and 0.08 % of the oral administered dose, respectively. This excretion of NOMAC into bile, urine, and feces after study indicated that NOMAC had a widespread distribution dosing were investigated. The results showed that NOMAC in tissues, including ovary, pituitary, and hypothalamus, was rapidly absorbed after oral administration, with tmax of which are main target tissues where NOMAC inhibits ovu- lation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation Q. Huang and X. Chen contributed equally to this work. was found in the drug elimination; however, it did not sig- Electronic supplementary material The online version of this nificantly affect tmax. article (doi:10.1007/s13318-014-0224-7) contains supplementary material, which is available to authorized users. Keywords Nomegestrol acetate Á NOMAC Á Q. Huang (&) Pharmacokinetics Á Tissue distribution Á Excretion Á HPLC State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Abbreviations Shanghai 201203, China NOMAC Nomegestrol acetate e-mail: [email protected] HPLC High-pressure liquid chromatography X. Chen AUC Area under the plasma concentration–time Department of Research and Development, Pharmaceutics curve International, Inc., Hunt Valley, MD 21031, USA CL Clearance C Y. Zhu Á L. Cao (&) max Maximum plasma concentration Department of Reproductive Pharmacology, Shanghai Institute V/F Apparent distribution volume of Planned Parenthood Research, Shanghai 200032, China t1=2b Terminal half-life e-mail: [email protected] tmax Time to maximum plasma concentration J. E. Riviere Ka Absorption rate constant Institute of Computational Comparative Medicine, Kansas State K10 Elimination rate constant University, Manhattan, KS 66506, USA 436 Eur J Drug Metab Pharmacokinet (2015) 40:435–442 K12 Distribution rate constant from the central showed a lack of proliferative activity in normal and can- compartment to the peripheral compartment cerous breast tissues and did not have a deleterious effect on K21 Distribution rate constant from the peripheral bone remodeling (Lello 2010; van Diepen 2012; Yang and compartment to the central compartment Plosker 2012). a Rate constant associated with the distribution Despite NOMAC has been used in humans in some phase of the concentration–time curve developed countries, limited information on pharmacoki- b Rate constant associated with the terminal netics, tissue distribution (especially for targeted organs phase of the concentration–time curve including ovary, uterus, hypothalamic, and pituitary), and excretion of NOMAC following a single oral administration in animals and humans was available (or disclosed) in the 1 Introduction literature due to confidential reasons. In this study, RP-HPLC method was adopted to determine NOMAC concentrations in Nomegestrol acetate (NOMAC) is a 19-norprogesterone rat biological matrices, including plasma, tissues, urine, derivative with a high progestational activity, first reported feces, and bile. The pharmacokinetic profiles of NOMAC in by Miyake and Rooks (1966). It is an orally active pro- female rats were investigated, including (1) the plasma gestogen with a favorable tolerability profile and neutral pharmacokinetics of NOMAC; (2) the tissue distribution of metabolic characteristics (Lello 2010). NOMAC is NOMAC; (3) the excretion of NOMAC in bile, urine, and designed to bind selectively for the progesterone receptor feces after oral administration. The results were also useful and lacks significant affinity with other steroid receptors, for new formulation development in the future. showing strong antiestrogenic and antigonadotropic activ- ity, but without androgenic or glucocorticoid properties (Lello 2010; van Diepen 2012; Ruan et al. 2012; Yang and 2 Materials and methods Plosker 2012). Unlike some other progestogens, the an- tigonadotropic effect of NOMAC is mediated at the 2.1 Chemicals and reagents hypothalamic and pituitary level (Couzinet et al. 1999). In in vitro functional assay, nanomolar affinity of NOMAC (lot no. 980616, purity [99.2 %, Fig. 1) was NOMAC was demonstrated in radioligand binding with gifted from School of Pharmacy, Fudan University Medical cytosolic progesterone receptor in human endometrium Center (Shanghai, China). Two internal standards (IS) (Botella et al. 1988) and breast tissue (Duc et al. 1990), and included flutamide (lot no. 981217, purity [99.2 %), pur- the potency of NOMAC was greater than progesterone. chased from Fudan Forward Pharmaceutical Co., Ltd NOMAC had no agonist or antagonist activity at a or b (Shanghai, China) and mifepristone (lot no. 980607, purity estrogen or mineralocorticoid receptors in Hela cells (a [99.8 %), obtained from Zhejiang Xianju Junye Pharma- human cervical carcinoma cell line) or CHO cells trans- ceutical Co., Ltd (Zhejiang, China). Methanol (HPLC fected with human steroid receptors (Merk Sharp and grade) was purchased from Shanghai Chemical Reagent Dohme (Australia) Pty Limited 2011). In addition, NO- Research Institute Co., Ltd (Shanghai, China). All other MAC inhibited the estrogen-induced stimulation of pro- chemicals and solvents were of the highest grade of com- gesterone receptor expression in T47-D human breast mercially available materials. Purified water obtained via a cancer cells in vitro (van Diepen 2012). Milli-Q system (Millipore, Bedford, MA, USA) was used NOMAC has been approved in Europe and Australia and throughout the experiments. widely used for the treatment of gynecological disorders (menstrual disturbances, dysmenorrhoea, and premenstrual 2.2 In vivo animal experiment syndrome) (Alsina 2010) and for hormone replacement therapy (HRT) in combination with estradiol (E2) for the Healthy Sprague–Dawley female rats weighing 200–320 g relief of post-menopausal symptoms (Shields-Botella et al. (certificate no. 02-49-2) were purchased from Shanghai 2003). At a dosage of 1.25 mg/day, NOMAC inhibited SLAC Laboratory Animal Co., Ltd. (Shanghai, China). ovulation while follicle growth was not affected; at a dosage Upon arrival in the laboratory, each animal was evaluated of 2.5 or 5 mg/day, both ovulation and follicle development by a laboratory veterinarian. The selected healthy female were significantly suppressed (Bazin et al. 1987). The studies rats were allowed to acclimate for at least 1 week before on NOMAC/E2 as a combined oral contraceptive (COC) the experiments. The animal room was maintained at showed that NOMAC preserved the beneficial hemostatic 25 ± 2 °C and 50–70 % relative humidity with 12 h light/ effects of estrogen and had a neutral or beneficial effect on dark cycles. Feed and municipal water were provided lipid profiles, while not changing body weight and having no ad libitum, except when feed was withdrawn *12 h before adverse effects on glucose metabolism. In addition, NOMAC dosing. The experiments were carried out in compliance Eur J Drug Metab Pharmacokinet (2015) 40:435–442 437 20 mg/kg. One additional rat was killed pre-dose to pro- vide blank control tissues. The animals were killed at 1, 2, or 4 h after the dosing (group 2 in Table 1). The tissues, including liver, kidney, stomach, brain, heart, lung, muscle, ovary, pituitary, hypothalamus, spleen, and uterus, were promptly removed and washed with saline solution to remove any residual blood. Each tissue sample (*0.5 g) was homogenized with 1.5 mL saline using Polytron PT- MR 3000 homogenizer (Kinematica AG, Switzerland) and the leftover on the homogenizer was washed with 0.5 mL saline and transferred to the same tube. Each sample was added with 10 lL flutamide (IS). NOMAC was isolated Fig. 1 Chemical structure of NOMAC from the homogenate as described previously for the plasma samples and stored at -80 °C until further analysis with Chinese Regulations for the Care and Use of Exper- (within 4 weeks). imental Animals. At the end of the experiment, pentobar- bital sodium was used for the euthanasia of the animals. 2.5
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