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 ovulation. 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 activity, 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 antigonadotropic 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 Metabolism and excretion studies

2.3 Plasma collection and NOMAC extraction Three female rats were orally administered a single dose of NOMAC at 20 mg/kg in a solution of saline (0.5 % Female rats were assigned randomly into three groups (five Tween-80). The rats (n = 3) were then placed into separate rats per group) and received 10, 20, and 40 mg/kg NOMAC in metabolic cages designed for the separation and collection a solution of saline (0.5 % Tween-80), respectively, through of urine and feces. Urine and feces were collected 3 h oral administration. By cutting the tails, blood samples before the dosing and 0–6, 6–12, (or 0–12), 12–24, 24–48, (800 lL) were collected into a clean test tube containing and 48–74 h after the dosing (group 3 and 4 in Table 1). sodium heparin before and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 h after Both urine and feces were collected in separate containers drug administration (group 1 in Table 1). Plasma was pre- surrounded by ice and then frozen at -80 °C at the end of pared by centrifugation at 3,000 rpm for 5 min after the blood each collection interval for further analysis (within samples were placed for 30 min, and then stored at -80 °C 4 weeks). until further analysis (within 4 weeks). Polyethylene tubes were surgically cannulated into the Extraction of NOMAC from plasma involved the addi- bile duct of female rats (n = 5). A 20 mg/kg dose of tion of 10 lL (containing total 1 lg) flutamide (IS) and NOMAC in a solution of saline (0.5 % Tween-80) was 3.0 mL diethyl ether into 500 lL of plasma sample (6:1, orally administered to the rats. Bile was collected into v/v) in 5 mL centrifuging glass tube and vortex mixing for successive vials on ice at 3 h before the dosing as a blank 1 min. The mixed samples were equilibrated at room control and at 0–2, 2–4, 4–8, 8–12, 12–24, 24–36, and temperature for 5 min, extracted twice with diethyl ether 36–48 h after the dosing (group 5 in Table 1). The bile (3.0 mL) with vortex mixing for 5 min each time, and then samples were stored at -80 °C for further analysis (within centrifuged at 3,000 rpm for 5 min. The organic and 4 weeks). The volumes of urine and bile, and dry weight of aqueous layers were separated by allowing the mixture to feces during each collection period were measured before stand in room temperature for 10 min. The top (organic) being stored in the refrigerator (Table 1). layer (2.5 mL) was transferred to glass tube and evaporated Before HPLC analysis, the urine sample was added with to dryness under a stream of nitrogen at 40 °C. The dried 20 lL (containing 2 lg) mifepristone as IS. After liquid– residue was then reconstituted with 30 lL of mobile phase liquid extraction with diethyl ether for three times, the (methanol: water = 70:30, v/v) and centrifuged at organic layers were evaporated to dryness under a stream 10,000 rpm for 5 min. After vortex mixing for 1 min, a of nitrogen at 40 °C. The residue was reconstituted in 20-lL aliquot was injected into HPLC system for analysis. 30 lL mobile phase and then centrifuged at 10,000 rpm for 5 min after vortex mixing for 1 min. Twenty microliter aliquot of the supernatant was injected into the HPLC 2.4 Tissue distribution studies system. Fecal samples (50 mg) were dried at 80 °C for 2 h, and then soaked in 1 mL methanol at 4 °C for 24 h. Five Fifteen female rats were divided randomly into three hundred microliters of supernatant was transferred and groups (five rats per group) and orally administered NO- 20 lL mifepristone (containing 2 lg) was added as IS. The MAC in a solution of saline (0.5 % Tween-80) at a dose of mixed samples were vertically blended for 2 min and then 438 Eur J Drug Metab Pharmacokinet (2015) 40:435–442

Table 1 Protocol for the pharmacokinetic study of NOMAC in rats Group Tissues n Route Dose (mg/kg) Collection times

1 Plasma 15 Oral 10, 20, 40 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h 2 Tissues 15 Oral 20 1, 2, and 4 h 3 Urine 3 Oral 20 –3–0, 0–6, 6–12, 12–24, 24–48 and 48–72 h 4 Feces 3 Oral 20 –3–0, 0–12, 12–24, 24–48 and 48–72 h 5 Bile 5 Oral 20 –3–0, 0–2, 2–4, 4–8, 8–12, 12–24, 24–36, and 36–48 h extracted as described previously for urine. Bile sample in female rats was shown in Fig. 3 and the pharmacokinetic was subjected to the same procedure as described for urine. parameters were calculated and summarized in Table 2. There were no significant differences in pharmacokinetic 2.6 HPLC analysis parameters compared with groups of 10, 20, and 40 mg/kg, except AUC and Cmax. Both AUC and Cmax exhibited Samples were analyzed using WatersÒ system equipped linear increase with the dose administered (r2 [ 0.98, with binary pump, on-line vacuum degasser, autosampler, p \ 0.01). The Cmax of NOMAC was obtained at 1–2 h Ò column compartment, UV detector, and Waters Millen- (tmax) after dosing, and the drug concentration decreased Ò nium 32 software, as described previously (Huang et al. slowly after Cmax.Thet1=2b values for NOMAC were 2000, 2014). Chromatographic separation was achieved on 13.14 ± 3.70, 9.33 ± 4.82, and 9.93 ± 3.71 h for dosing Ò a lBondapak -C18 column (300 9 3.9 mm, 5 lm; Waters groups of 10, 20, and 40 mg/kg, respectively. The values of Ò Instruments, Marlborough, MA) and a lBondapak -C18 V/F and CL, as well as K10, were relatively constant guard column. An isocratic mobile phase consisted of a compared with three groups. The K12 and K21 values were mixture of methanol and water (70:30, v/v, %) with a flow very similar in the same dosing group, and no significant rate of 1.2 mL/min, and the column temperature was difference was observed among different groups maintained at 25 ± 2 °C throughout the analysis. The (p [ 0.05). eluent was detected by UV detector with the wavelength set at 293 nm. The HPLC chromatograms of the extracted 3.2 Tissue distribution rat plasma, bile, and urine samples with the presence of IS were shown in Fig. 2. Tissue distribution studies in Sprague–Dawley female rats after oral dose of 20 mg/kg revealed wide tissue distribu- 2.7 Pharmacokinetic and statistical analysis tion (Fig. 4). In three sampling times (1, 2, and 4 h), the highest tissue concentrations of NOMAC were observed at The data of plasma concentration versus time for NOMAC 2 h after oral dosing, excluding stomach, pituitary, and were analyzed using PK-GRAPH package (Yi 1992). The hypothalamus, whose highest concentrations appeared at pharmacokinetic parameters were estimated by appropriate 1 h. The stomach samples exhibited the highest drug compartmental methods. The goodness of fit and the most exposure. The mean Cmax values of ovary, liver, pituitary, appropriate model were determined by accessing the ran- hypothalamus, and kidney were 6.4, 4.8, 3.9, 2.5, and domness of the scatter of actual data points around the 2.2 lg/g, respectively. Other tissues that displayed relative fitted function. The Student’s t test was used to analyze high exposure were lung, heart, brain, and spleen. NOMAC differences between two groups. The difference in two concentrations in muscle and uterus were very low (1.1 and groups of data with p-value of \0.05 or 0.01 was consid- 1.0 lg/g, respectively). ered significant. The data were presented as mean ± SD. 3.3 Urinary, fecal, and biliary excretion

3 Results The NOMAC excretion-time proﬁles for the urine and feces within 72 h and the bile within 48 h following 3.1 Plasma pharmacokinetics 20 mg/kg oral administration were described in Fig. 5. The urinary and fecal excretions of NOMAC were completed Plasma concentration versus time was modeled by PK- before 24 h, when the cumulative excretion curve reached GRAPH package and the best ﬁt was achieved by a two- the maximum. However, biliary excretion seemed to con- compartment model. A plot of mean plasma drug con- tinue after 48 h according to the ascending curve. The centration versus time for oral administration of NOMAC cumulative percentages of intact NOMAC excreted Eur J Drug Metab Pharmacokinet (2015) 40:435–442 439

Fig. 2 Representative HPLC chromatograms of the extracted plasma (a) biliary (b) urinary (c) and fecal (d) samples obtained from rats following a single oral dose of 20 mg/kg of NOMAC. Internal standards (IS) in plasma and biliary samples were ﬂutamide; IS in urinary and fecal samples were mifepristone

Fig. 3 Mean plasma concentration–time proﬁle of NOMAC after oral administration of 10, 20, and 40 mg/kg of NOMAC to rats. At 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h following NOMAC oral administration, plasma samples were collected and processed for HPLC determination. Each data point represents mean ? SD of ﬁve rats 440 Eur J Drug Metab Pharmacokinet (2015) 40:435–442

Table 2 Pharmacokinetic parameters following NOMAC administration to rats Parameter Units Mean ± SD at different doses (mg/kg) 10 20 40

-1 • Ka h 3.87 ± 2.63 1.06 ± 1.06 1.09 ± 0.53 a h-1 1.33 ± 1.62 1.01 ± 0.82 0.37 ± 0.14• b h-1 0.06 ± 0.02 0.09 ± 0.03 0.07 ± 0.02• • t1=2ðKaÞ h 0.25 ± 0.15 1.49 ± 1.09 0.74 ± 0.29 • t1=2a h 1.63 ± 1.89 1.65 ± 1.95 2.09 ± 0.90 • t1=2b h 13.14 ± 3.70 9.33 ± 4.82 9.93 ± 3.71 -1 • K10 h 0.12 ± 0.05 0.17 ± 0.11 0.16 ± 0.10 -1 • K12 h 0.73 ± 1.06 0.55 ± 0.68 0.10 ± 0.08 -1 • K21 h 0.54 ± 0.54 0.35 ± 0.29 0.18 ± 0.01 V=F L/kg 68.46 ± 53.58 58.95 ± 33.22 52.60 ± 20.59• CL L/h/kg 5.42 ± 1.09 5.87 ± 0.34 5.44 ± 2.24• -1 • tmax h 0.99 ± 0.34 2.68 ± 1.56 2.50 ± 0.60** # Cmax ng/mL 143 ± 28 280 ± 91* 589 ± 65** AUC ng 9 h/mL 1,910 ± 404 3,417 ± 188** 8,698 ± 4,421**# n=5per group; differences of pharmacokinetic parameters between groups 20 mg/kg (or 40 mg/kg) and 10 mg/kg: p [ 0.05; * p \ 0.05; ** p \ 0.01; differences of pharmacokinetic parameters between groups 40 and 20 mg/kg: • p [ 0.05; # p \ 0.01

through the urine and feces within 72 h were 0.03 ± 0.01 and 1.06 ± 0.55 %, respectively. The cumulative per- centage excreted to bile was 0.08 ± 0.01 % within 48 h.

4 Discussion

This study showed that NOMAC is rapidly absorbed into the bloodstream, reaching maximum blood concentrations at 1–2 h after dosing, which was similar to that observed in mice, cynomogus monkeys (Merk Sharp and Dohme (Australia) Pty Limited 2011), and humans(1.5–2 h) (Gerrits et al. 2013). NOMAC was distributed fast in tissues and excreted through feces and urine. The hepato- enteral circulation occurred during drug elimination. By comparing pharmacokinetic parameters of NOMAC at 10, 20, and 40 mg/kg using the Student’s t test, no sig- niﬁcant difference was observed except for Cmax and AUC, which were dose-proportional. This suggested that NOMAC exhibited linear ﬁrst-order pharmacokinetic characteristics and no saturation of metabolism occurred in the dose range of 10–40 mg/kg. The value of V/F in rats was 60 L/kg, 2.5-fold larger than in humans (27 L/kg) (Gerrits et al. 2013), which follows allometric principle. The t1=2b of NOMAC was about 10 h, shorter than human t1=2b (42 h) (Gerrits et al. 2013) due to the faster and more Fig. 4 Tissue distribution of NOMAC in rats (n = 5) after a single extensive metabolism of NOMAC in animals compared oral dose of 20 mg/kg. At 1, 2, and 4 h following oral administration, with humans (Merk Sharp and Dohme (Australia) Pty tissue samples were collected and processed for HPLC determination. Limited 2011). Values are presented as mean ? SD Eur J Drug Metab Pharmacokinet (2015) 40:435–442 441

Table 3 The structures of possible metabolites of NOMAC observed in rat plasma Metabolites no# Metabolite structure

Metabolite #1

Metabolite #2

Fig. 5 Cumulative excretion of NOMAC in fences, urine, and bile Metabolite #3 following a single oral dose of 20 mg/kg. Feces and urine samples were collected at 6, 12, 24, 48, and 72 h and bile samples were collected at 2, 4, 8, 12, 24, 36, and 48 h. Values are presented as mean ? SD (urine and bile) or mean ± SD (feces)

The distribution of NOMAC in tissues was rapid, with the highest concentration observed at 2 h post-administration in most tissues. NOMAC had widespread tissue dis- Metabolite #4 tribution in different tissues, including stomach, ovary, liver, pituitary, kidney and hypothalamus, lung, heart, brain, spleen, muscle, and uterus. The high NOMAC concentration appeared in hypothalamus, pituitary, and brain at 2 h, which indicated that NOMAC can transfer across the blood–brain barrier (BBB) easily. In addition, high levels of NOMAC were observed in the organs Metabolite #5 including ovary, hypothalamus, and pituitary, which is consistent with the distribution to receptors in target tissues (Bazin et al. 1987; Botella et al. 1986, 1988; Couzinet et al. 1999; Duc et al. 1990). The concentrations of NOMAC in the urine were analyzed till their concentrations decreased below HPLC Nomegestrol (minor) detection limit. About 0.08 % cumulative amount of NOMAC was eliminated via biliary excretion within 48 h; the excretion was projected to keep active after 48 h according to the slope of the cumulative excretion curve at 48 h, whereas little amount of NOMAC was found in feces after 48 h, and negligible NOMAC excretion was observed in urine after 24 h. The polar nature of NOMAC with good liposolubility prevents drug excretion through the kidney. These findings are consistent with the previous report that compounds whose molecular weight ranged between 150 and 700 demonstrated an increase in the proportion of the enterohepatic circulation of NOMAC did not signifi- compounds excreted in the bile versus urine when the cantly change tmax because (1) only small portion (*15 %) molecular weight increased (Calabrese 1983). However, of NOMAC in the bloodstream undergoes enterohepatic 442 Eur J Drug Metab Pharmacokinet (2015) 40:435–442 circulation; (2) the excretion rates of NOMAC in the bile mineralocorticoid and glucocorticoid cytosolic receptors. J Phar- decreased after 2 h, which can be observed by the slopes of macol 17:699–706 Botella J, Paris J, Duc I, Lahlou B (1988) Nomegestrol acetate the biliary cumulative excretion curve in Fig. 5. The binding to cytosolic progesterone receptor in human endome- excretion of intact NOMAC in rat was detected only at low trium. Med Sci Res 16:299–300 concentrations in feces, urine, and bile, similar to that Calabrese EJ (1983) Principles of Animal Extrapolation. Wiley, New observed in monkeys and humans (Merk Sharp and Dohme York Couzinet B, Young J, Kujas M, Meduri G, Brailly S, Thomas JL, (Australia) Pty Limited 2011; Gerrits et al. 2013). Chanson P, Schaison G (1999) Theantigonadotropic activity of a NOMAC is metabolized primarily by hepatic CYP3A4 19-nor-progesterone derivative is exerted both at the hypotha- and CYP3A5, and a possible contributory role by lamic and pituitary levels in women. J Clin Endocrinol Metab CYP2C19 and CYP2C8 (Yang and Plosker 2012). 84:4191–4196 Duc I, Botella J, Gillet JY, Duforestel T, Paris J (1990) Nomegestrol NOMAC is metabolized into several hydroxylated metab- acetate binding to human breast tissue. Med Sci Res 18:57–58 olites and subsequently conjugated with glucuronide or Ezan E, Benech H, Bucourt R, Ardouin T, Tchernatinsky C, Thomas sulfate (Lello 2010), which accounts for only 1.08 or\1% JL, Paris J, Grognet JM (1993) Enzyme immunoassay for of intact NOMAC being detected in feces, urine or bile nomegestrol acetate in human plasma. J Steroid Biochem Mol Biol 46:507–514 samples of rats. All metabolites of NOMAC had little or no Gerrits MG, Schnabel PG, Post TM, Peeters PA (2013) Pharmaco- effects on progesterone receptor activity (Lello 2010). The kinetic profile of nomegestrol acetate and 17b-estradiol after possible structures of NOMAC metabolites in rats were multiple and single dosing in healthy women. Contraception shown in Table 3 (Merk Sharp and Dohme (Australia) Pty 87:193–200 Gibaldi M, Perrier D (1982) Pharmacokinetics. Marcel Dekker, New Limited 2011). York Huang Q, Cao L, Gu Z (2000) RP-HPLC determination of nomegestrol acetate in plasma of rabbit. Chin J Pharm Anal 20:379–380 5 Conclusions Huang Q, Chen X, Zhu Y, Cao L (2014) Development and validation of an HPLC method for the quantitation of nomegestrol acetate in biological matrices of rats. 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