ORIGINAL PAPER

Pharmacokinetics, tissue distribution, and excretionof nomegestrol acetate in female rats

Qingbiao Huang • Xiaoke Chen • Yan Zhu •

Lin Cao • Jim E. Riviere

Received: 16 May 2014 / Accepted: 20 August 2014

� Springer International Publishing Switzerland 2014

Abstract Nomegestrol acetate (NOMAC), a synthetic

progestogen derived from 19-norprogesterone, is an orally

active drug with a strong affinity for the progesterone

receptor. NOMAC inhibits ovulation and is devoid of

undesirable androgenic and estrogenic activities. The aim

of this study was to evaluate the pharmacokinetics, tissue

distribution, and excretion of NOMAC in female rats.

Sprague–Dawley female rats were orally administered a

single dose of NOMAC (10, 20 or 40 mg/kg) and drug

plasma concentrations at different times were determined

by RP-HPLC. Tissue distribution at 1, 2, and 4 h and

excretion of NOMAC into bile, urine, and feces after

dosing were investigated. The results showed that NOMAC

was rapidly absorbed after oral administration, with tmax of

1–2 h. The plasma concentration–time curves were fitted in

a two-compartment model. The exposure to NOMAC (Cmax

and AUC) increased dose proportionally from 10 to 40 mg/

kg. The average CL and t1=2b were 5.58 L/(h�kg) and 10.8 h,

respectively. The highest concentrations of NOMAC in

ovary, liver, kidney, lung, heart, brain, spleen, muscle, and

uterus were observed at 2 h, whereas the highest concen-

trations in stomach, pituitary, and hypothalamus appeared at

1 h. The total cumulative excretion of NOMAC in feces

(0–72 h), urine (0–72 h), and bile (0–48 h) was*1.06, 0.03,

and 0.08 % of the oral administered dose, respectively. This

study indicated that NOMAC had a widespread distribution

in tissues, including ovary, pituitary, and hypothalamus,

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

was found in the drug elimination; however, it did not sig-

nificantly affect tmax.

Keywords Nomegestrol acetate � NOMAC �Pharmacokinetics � Tissue distribution � Excretion � HPLC

Abbreviations

NOMAC Nomegestrol acetate

HPLC High-pressure liquid chromatography

AUC Area under the plasma concentration–time

curve

CL Clearance

Cmax Maximum plasma concentration

V/F Apparent distribution volume

t1=2b Terminal half-life

tmax Time to maximum plasma concentration

Ka Absorption rate constant

K10 Elimination rate constant

Q. Huang and X. Chen contributed equally to this work.

Electronic supplementary material The online version of thisarticle (doi:10.1007/s13318-014-0224-7) contains supplementarymaterial, which is available to authorized users.

Q. Huang (&)

State Key Laboratory of Drug Research, Shanghai Institute of

Materia Medica, Chinese Academy of Sciences,

Shanghai 201203, China

e-mail: tommyqbhuang@gmail.com

X. Chen

Department of Research and Development, Pharmaceutics

International, Inc., Hunt Valley, MD 21031, USA

Y. Zhu � L. Cao (&)

Department of Reproductive Pharmacology, Shanghai Institute

of Planned Parenthood Research, Shanghai 200032, China

e-mail: caolin21@163.com

J. E. Riviere

Institute of Computational Comparative Medicine, Kansas State

University, Manhattan, KS 66506, USA

Eur J Drug Metab Pharmacokinet

DOI 10.1007/s13318-014-0224-7

K12 Distribution rate constant from the central

compartment to the peripheral compartment

K21 Distribution rate constant from the peripheral

compartment to the central compartment

a Rate constant associated with the distribution

phase of the concentration–time curve

b Rate constant associated with the terminal

phase of the concentration–time curve

1 Introduction

Nomegestrol acetate (NOMAC) is a 19-norprogesterone

derivative with a high progestational activity, first reported

by Miyake and Rooks (1966). It is an orally active pro-

gestogen with a favorable tolerability profile and neutral

metabolic characteristics (Lello 2010). NOMAC is

designed to bind selectively for the progesterone receptor

and lacks significant affinity with other steroid receptors,

showing strong antiestrogenic and antigonadotropic activ-

ity, but without androgenic or glucocorticoid properties

(Lello 2010; van Diepen 2012; Ruan et al. 2012; Yang and

Plosker 2012). Unlike some other progestogens, the an-

tigonadotropic effect of NOMAC is mediated at the

hypothalamic and pituitary level (Couzinet et al. 1999).

In in vitro functional assay, nanomolar affinity of

NOMAC was demonstrated in radioligand binding with

cytosolic progesterone receptor in human endometrium

(Botella et al. 1988) and breast tissue (Duc et al. 1990), and

the potency of NOMAC was greater than progesterone.

NOMAC had no agonist or antagonist activity at a or bestrogen or mineralocorticoid receptors in Hela cells (a

human cervical carcinoma cell line) or CHO cells trans-

fected with human steroid receptors (Merk Sharp and

Dohme (Australia) Pty Limited 2011). In addition, NO-

MAC inhibited the estrogen-induced stimulation of pro-

gesterone receptor expression in T47-D human breast

cancer cells in vitro (van Diepen 2012).

NOMAC has been approved in Europe and Australia and

widely used for the treatment of gynecological disorders

(menstrual disturbances, dysmenorrhoea, and premenstrual

syndrome) (Alsina 2010) and for hormone replacement

therapy (HRT) in combination with estradiol (E2) for the

relief of post-menopausal symptoms (Shields-Botella et al.

2003). At a dosage of 1.25 mg/day, NOMAC inhibited

ovulation while follicle growth was not affected; at a dosage

of 2.5 or 5 mg/day, both ovulation and follicle development

were significantly suppressed (Bazin et al. 1987). The studies

on NOMAC/E2 as a combined oral contraceptive (COC)

showed that NOMAC preserved the beneficial hemostatic

effects of estrogen and had a neutral or beneficial effect on

lipid profiles, while not changing body weight and having no

adverse effects on glucose metabolism. In addition, NOMAC

showed a lack of proliferative activity in normal and can-

cerous breast tissues and did not have a deleterious effect on

bone remodeling (Lello 2010; van Diepen 2012; Yang and

Plosker 2012).

Despite NOMAC has been used in humans in some

developed countries, limited information on pharmacoki-

netics, tissue distribution (especially for targeted organs

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

literature due to confidential reasons. In this study, RP-HPLC

method was adopted to determine NOMAC concentrations in

rat biological matrices, including plasma, tissues, urine,

feces, and bile. The pharmacokinetic profiles of NOMAC in

female rats were investigated, including (1) the plasma

pharmacokinetics of NOMAC; (2) the tissue distribution of

NOMAC; (3) the excretion of NOMAC in bile, urine, and

feces after oral administration. The results were also useful

for new formulation development in the future.

2 Materials and methods

2.1 Chemicals and reagents

NOMAC (lot no. 980616, purity [99.2 %, Fig. 1) was

gifted from School of Pharmacy, Fudan University Medical

Center (Shanghai, China). Two internal standards (IS)

included flutamide (lot no. 981217, purity [99.2 %), pur-

chased from Fudan Forward Pharmaceutical Co., Ltd

(Shanghai, China) and mifepristone (lot no. 980607, purity

[99.8 %), obtained from Zhejiang Xianju Junye Pharma-

ceutical Co., Ltd (Zhejiang, China). Methanol (HPLC

grade) was purchased from Shanghai Chemical Reagent

Research Institute Co., Ltd (Shanghai, China). All other

chemicals and solvents were of the highest grade of com-

mercially available materials. Purified water obtained via a

Milli-Q system (Millipore, Bedford, MA, USA) was used

throughout the experiments.

2.2 In vivo animal experiment

Healthy Sprague–Dawley female rats weighing 200–320 g

(certificate no. 02-49-2) were purchased from Shanghai

SLAC Laboratory Animal Co., Ltd. (Shanghai, China).

Upon arrival in the laboratory, each animal was evaluated

by a laboratory veterinarian. The selected healthy female

rats were allowed to acclimate for at least 1 week before

the experiments. The animal room was maintained at

25 ± 2 �C and 50–70 % relative humidity with 12 h light/

dark cycles. Feed and municipal water were provided

ad libitum, except when feed was withdrawn *12 h before

dosing. The experiments were carried out in compliance

Eur J Drug Metab Pharmacokinet

with Chinese Regulations for the Care and Use of Exper-

imental Animals. At the end of the experiment, pentobar-

bital sodium was used for the euthanasia of the animals.

2.3 Plasma collection and NOMAC extraction

Female rats were assigned randomly into three groups (five

rats per group) and received 10, 20, and 40 mg/kg NOMAC in

a solution of saline (0.5 % Tween-80), respectively, through

oral administration. By cutting the tails, blood samples

(800 lL) were collected into a clean test tube containing

sodium heparin before and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 h after

drug administration (group 1 in Table 1). Plasma was pre-

pared by centrifugation at 3,000 rpm for 5 min after the blood

samples were placed for 30 min, and then stored at -80 �C

until further analysis (within 4 weeks).

Extraction of NOMAC from plasma involved the addi-

tion of 10 lL (containing total 1 lg) flutamide (IS) and

3.0 mL diethyl ether into 500 lL of plasma sample (6:1,

v/v) in 5 mL centrifuging glass tube and vortex mixing for

1 min. The mixed samples were equilibrated at room

temperature for 5 min, extracted twice with diethyl ether

(3.0 mL) with vortex mixing for 5 min each time, and then

centrifuged at 3,000 rpm for 5 min. The organic and

aqueous layers were separated by allowing the mixture to

stand in room temperature for 10 min. The top (organic)

layer (2.5 mL) was transferred to glass tube and evaporated

to dryness under a stream of nitrogen at 40 �C. The dried

residue was then reconstituted with 30 lL of mobile phase

(methanol: water = 70:30, v/v) and centrifuged at

10,000 rpm for 5 min. After vortex mixing for 1 min, a

20-lL aliquot was injected into HPLC system for analysis.

2.4 Tissue distribution studies

Fifteen female rats were divided randomly into three

groups (five rats per group) and orally administered NO-

MAC in a solution of saline (0.5 % Tween-80) at a dose of

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

from the homogenate as described previously for the

plasma samples and stored at -80 �C until further analysis

(within 4 weeks).

2.5 Metabolism and excretion studies

Three female rats were orally administered a single dose of

NOMAC at 20 mg/kg in a solution of saline (0.5 %

Tween-80). The rats (n = 3) were then placed into separate

metabolic cages designed for the separation and collection

of urine and feces. Urine and feces were collected 3 h

before the dosing and 0–6, 6–12, (or 0–12), 12–24, 24–48,

and 48–74 h after the dosing (group 3 and 4 in Table 1).

Both urine and feces were collected in separate containers

surrounded by ice and then frozen at -80 �C at the end of

each collection interval for further analysis (within

4 weeks).

Polyethylene tubes were surgically cannulated into the

bile duct of female rats (n = 5). A 20 mg/kg dose of

NOMAC in a solution of saline (0.5 % Tween-80) was

orally administered to the rats. Bile was collected into

successive vials on ice at 3 h before the dosing as a blank

control and at 0–2, 2–4, 4–8, 8–12, 12–24, 24–36, and

36–48 h after the dosing (group 5 in Table 1). The bile

samples were stored at -80 �C for further analysis (within

4 weeks). The volumes of urine and bile, and dry weight of

feces during each collection period were measured before

being stored in the refrigerator (Table 1).

Before HPLC analysis, the urine sample was added with

20 lL (containing 2 lg) mifepristone as IS. After liquid–

liquid extraction with diethyl ether for three times, the

organic layers were evaporated to dryness under a stream

of nitrogen at 40 �C. The residue was reconstituted in

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

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

hundred microliters of supernatant was transferred and

20 lL mifepristone (containing 2 lg) was added as IS. The

mixed samples were vertically blended for 2 min and then

Fig. 1 Chemical structure of NOMAC

Eur J Drug Metab Pharmacokinet

extracted as described previously for urine. Bile sample

was subjected to the same procedure as described for urine.

2.6 HPLC analysis

Samples were analyzed using Waters� system equipped

with binary pump, on-line vacuum degasser, autosampler,

column compartment, UV detector, and Waters� Millen-

nium�32 software, as described previously (Huang et al.

2000, 2014). Chromatographic separation was achieved on

a lBondapak�-C18 column (300 9 3.9 mm, 5 lm; Waters

Instruments, Marlborough, MA) and a lBondapak�-C18

guard column. An isocratic mobile phase consisted of a

mixture of methanol and water (70:30, v/v, %) with a flow

rate of 1.2 mL/min, and the column temperature was

maintained at 25 ± 2 �C throughout the analysis. The

eluent was detected by UV detector with the wavelength

set at 293 nm. The HPLC chromatograms of the extracted

rat plasma, bile, and urine samples with the presence of IS

were shown in Fig. 2.

2.7 Pharmacokinetic and statistical analysis

The data of plasma concentration versus time for NOMAC

were analyzed using PK-GRAPH package (Yi 1992). The

pharmacokinetic parameters were estimated by appropriate

compartmental methods. The goodness of fit and the most

appropriate model were determined by accessing the ran-

domness of the scatter of actual data points around the

fitted function. The Student’s t test was used to analyze

differences between two groups. The difference in two

groups of data with p-value of \0.05 or 0.01 was consid-

ered significant. The data were presented as mean ± SD.

3 Results

3.1 Plasma pharmacokinetics

Plasma concentration versus time was modeled by PK-

GRAPH package and the best fit was achieved by a two-

compartment model. A plot of mean plasma drug con-

centration versus time for oral administration of NOMAC

in female rats was shown in Fig. 3 and the pharmacokinetic

parameters were calculated and summarized in Table 2.

There were no significant differences in pharmacokinetic

parameters compared with groups of 10, 20, and 40 mg/kg,

except AUC and Cmax. Both AUC and Cmax exhibited

linear increase with the dose administered (r2 [ 0.98,

p \ 0.01). The Cmax of NOMAC was obtained at 1–2 h

(tmax) after dosing, and the drug concentration decreased

slowly after Cmax. The t1=2b values for NOMAC were

13.14 ± 3.70, 9.33 ± 4.82, and 9.93 ± 3.71 h for dosing

groups of 10, 20, and 40 mg/kg, respectively. The values of

V/F and CL, as well as K10, were relatively constant

compared with three groups. The K12 and K21 values were

very similar in the same dosing group, and no significant

difference was observed among different groups

(p [ 0.05).

3.2 Tissue distribution

Tissue distribution studies in Sprague–Dawley female rats

after oral dose of 20 mg/kg revealed wide tissue distribu-

tion (Fig. 4). In three sampling times (1, 2, and 4 h), the

highest tissue concentrations of NOMAC were observed at

2 h after oral dosing, excluding stomach, pituitary, and

hypothalamus, whose highest concentrations appeared at

1 h. The stomach samples exhibited the highest drug

exposure. The mean Cmax values of ovary, liver, pituitary,

hypothalamus, and kidney were 6.4, 4.8, 3.9, 2.5, and

2.2 lg/g, respectively. Other tissues that displayed relative

high exposure were lung, heart, brain, and spleen. NOMAC

concentrations in muscle and uterus were very low (1.1 and

1.0 lg/g, respectively).

3.3 Urinary, fecal, and biliary excretion

The NOMAC excretion-time profiles for the urine and

feces within 72 h and the bile within 48 h following

20 mg/kg oral administration were described in Fig. 5. The

urinary and fecal excretions of NOMAC were completed

before 24 h, when the cumulative excretion curve reached

the maximum. However, biliary excretion seemed to con-

tinue after 48 h according to the ascending curve. The

cumulative percentages of intact NOMAC excreted

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

Eur J Drug Metab Pharmacokinet

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

Eur J Drug Metab Pharmacokinet

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 tis-

sues 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

extensive metabolism of NOMAC in animals compared

with humans (Merk Sharp and Dohme (Australia) Pty

Limited 2011).

Fig. 4 Tissue distribution of NOMAC in rats (n = 5) after a single

oral dose of 20 mg/kg. At 1, 2, and 4 h following oral administration,

tissue samples were collected and processed for HPLC determination.

Values are presented as mean ? SD

Table 2 Pharmacokinetic parameters following NOMAC administration to rats

Parameter Units Mean ± SD at different doses (mg/kg)

10 20 40

Ka h-1 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�•

K10 h-1 0.12 ± 0.05 0.17 ± 0.11� 0.16 ± 0.10�•

K12 h-1 0.73 ± 1.06 0.55 ± 0.68� 0.10 ± 0.08�•

K21 h-1 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�•

tmax h-1 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 = 5 per 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

Eur J Drug Metab Pharmacokinet

The distribution of NOMAC in tissues was rapid, with

the highest concentration observed at 2 h post-administra-

tion in most tissues. NOMAC had widespread tissue dis-

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

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 ana-

lyzed till their concentrations decreased below HPLC

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

compounds excreted in the bile versus urine when the

molecular weight increased (Calabrese 1983). However,

the enterohepatic circulation of NOMAC did not signifi-

cantly change tmax because (1) only small portion (*15 %)

of NOMAC in the bloodstream undergoes enterohepatic

Table 3 The structures of possible metabolites of NOMAC observed

in rat plasma

Metabolites no# Metabolite structure

Metabolite #1

Metabolite #2

Metabolite #3

Metabolite #4

Metabolite #5

Nomegestrol (minor)

Fig. 5 Cumulative excretion of NOMAC in fences, urine, and bile

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)

Eur J Drug Metab Pharmacokinet

circulation; (2) the excretion rates of NOMAC in the bile

decreased after 2 h, which can be observed by the slopes of

the biliary cumulative excretion curve in Fig. 5. The

excretion of intact NOMAC in rat was detected only at low

concentrations in feces, urine, and bile, similar to that

observed in monkeys and humans (Merk Sharp and Dohme

(Australia) Pty Limited 2011; Gerrits et al. 2013).

NOMAC is metabolized primarily by hepatic CYP3A4

and CYP3A5, and a possible contributory role by

CYP2C19 and CYP2C8 (Yang and Plosker 2012).

NOMAC is metabolized into several hydroxylated metab-

olites and subsequently conjugated with glucuronide or

sulfate (Lello 2010), which accounts for only 1.08 or\1 %

of intact NOMAC being detected in feces, urine or bile

samples of rats. All metabolites of NOMAC had little or no

effects on progesterone receptor activity (Lello 2010). The

possible structures of NOMAC metabolites in rats were

shown in Table 3 (Merk Sharp and Dohme (Australia) Pty

Limited 2011).

5 Conclusions

NOMAC was fast absorbed, widely distributed throughout

tissues, eliminated in female rats via both fecal and renal

routes, and has a long terminal half-life. The results can be

useful for drug formulation development and pharmaco-

kinetic studies in humans.

Acknowledgments The authors would like to thank Gengdi You

and Rongfa Lu for excellent technical support. This work was

financially supported by Shanghai Modern Biology and Drug Industry

Development Foundation (No. 955419004).

Conflict of interest The authors report no conflict of interest. The

authors are responsible for the content and writing of the paper.

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