The mean serum NET concentrations observed 24 h after ingestion of the oral
contraceptive ranged from 0.3-o.7Ilg litre-' (1.I-204nmollitre-l
0.3-I.51Jg litre"! (1.3-5 .0nmollitre-l
Details ofa further radioimmunoassay for NET have been published by Back eral.
(1978) who raised an antibody of NET-3-carboxymethyloxime linked to bovine
serum albumin in rabbits. Results are presented on plasma concentrations ofNET in
40 women taking cornbinations of NEA + EE sampled 12 h after ingestion of the
tablet during multiple dosing. For women taking Img NEA + 501Jg EE, the mean
plasma NET concentrations was 5.91lg litre:' (l9 .8nmol litre:"), with a range of
1.6-15 .21Jg litrc! (504-5I.1nmol litre"). For women taking 3mg NEA + 50llg EE the
mean value was 8.31Jg litre-' (27 .9nmol litre-') with a range of 3.3-ll.2llg litre"
(l1.I-37 .6nmol litre:'). Finally, the women taking Img NET +201lg EE , the mean
plasma NET was 4.81lg litrc" (l6 .lnmol litre:") with a range of 3.6-6.01Jg litre"!
For women taking lrng NEA + 501Jg EE, the 12 h plasma NET concentration
showed a higher mean value (1.711Jg litre'"; 5.7nmollitre-l
treatment than during cycle I (O .58Ilg litre:': 1.9nmollitre-I
An investigation of the 12 h plasma NET concentration in three post-parturn
women studied on day I of the first cycle showed significantly higher values than in
nulliparous women also beginning treatment with the same oral contraceptive. The
plasma half-life ofNET in this study ranged from 6.1-12.3 hin six patients.
Measurements are also presented on sex hormone-binding globulin wh ich
increased in most women during the use of combined oral contraceptives. A good
receiving a combined O.c. containing 3mg NEA was only 104 times as high as that in
women taking a combined oral contraceptive containing Img NEA, it is possible that
the high dose of progestogen suppresses the oestrogen stimulated increase in sex
hormone-binding globulin, which is known to be a carrier protein for NET in human
A second paper from this group concerns the kinetics ofNET in women following
single doses. Back eral. (1978) have investigated plasma concentrations ofNET in six
healthy young women aged 21-33 years who received four different preparations
containing NET in a random order. The different preparations used were Img
NEA + 501Jg EE , 1.05mg NET, 3mg NEA + 501Jg EE and Img NET + 501Jg EE given
intravenously. Blood specimens were collected at intervals up to 24 h after dosing,
and NET measured by the same radioimmunoassay as described above. It reports
that NET kinetics were unaffected by concomitant administration ofEE, and that the
bioavailability of NET after an oral Img dose ranged from 47% to 73%, as compared
The plasma concentration decay slope fitted a two component open model with an
initial rapid decay, with a half-life of0.41-2.6 h, followed by a slower ß phase with
dose formulation (between 32% and 70%).
A study of NET pharmacokinetics in Indian women of different socio-economic
groups has been published by Prasad, Narasinga Rao , Sivakumar & Prema (1979).
An evaluation was conducted in 11 women belonging to a low socio-econornic group
and in 5 belonging to a high socio-economic group. A single oral dose ofO.35mg NET
was administered to each woman on an ernpty stornach. Blood specimens were
albumin conjugate. In all subjects, the peak serum concentration of NET occurred
within 1-2 h of ingestion, and NET levels then declined in an exponential manner.
The half-li fe of plasma NET in women of the low socio-economic group was
1.0 ± 0.42 hand 1.5 ± 0.28 h in the higher socio-econornic group. This difference is
statistically significant ofP < 0.05 .
In cornparison, in the study by Stanczyk 1'1 al. (1978) cited above, in American
women the half-life of the first disposition phase ranged from mean values of
2.2-4.4 h for the different commercial oral contraceptive formulations used in that
study. The peak NET values obtained in the Indian two groups were 7.7-12 .31Jg litre-'
(25 .9-41.3nmol litre') and 4.7-14.8~g litre! (l5 .8-49.7nmol litre-'). These values
appear to be significantly higher than the peaks observed in Arnerican women using
Prasad and colleagues (1979) observed a significant correlation between the
weight/theight)- x 100 index and the half-life of NET in all the women studied,
suggesting a role for nutritional status in the metabolic handling ofNET.
The metabolism ofNET has been compared at 14 different international centres by
Fotherby, Abdel-Rahman, deSouza , Coutinho, Koetsawang, Nukulkarn, Sheth,
Mapa, Gopalan, Plunkett, Brenner, Hickey, Grech, Lichtenberg, Gual, Malina,
Gornez-Rogers, Kwon , Kim, Chan, Rathnam, Landren & Shearman (1979) . Plasma
concentrations were measured at various times following a standard dose (I mg).
lnter-centre differences were of the same order as intra-centre differences and body
size did not appear to influence the rate of NET disappearance from blood. A
summary ofthe mean ranges found in this study is presented in Table 2.
Table 2 Plasma profile ofNET (Img p.o.)*
EDDA is rapidly deacetylated and oxidised to NET following administration to
humans. Walls, Vose, Horth & Palmer (1977) have discussed the radioimmunoassay
of plasma NET following oral tablets of Img EDDA + 501Jg EE taken by four normal
women. Peak concentrations of 7.2 to 15.31Jg litre-I (24 to 52 nmol litre'") were
achieved at 1.3 to 3.0 h after administration. Comparison of mean areas under the
plasma concentration-time curve indicated that the absorption of EDDA could be
monitored by measurements ofplasma NET.
A further study on bioavailability and pharmacokinetics of NET in women
receiving oral EDDA, has been published by Vose , Butler, Williams, Stafford,
NET responses in 12 healthy women aged 21-37 years who received either oral
contraceptives containing Img EDDA + 501Jg EE, or a solution containing EDA + EE
in ethanol. Using a balanced, eross-over study design, four treatment schedules were
given using oral contraceptive tablets from different batches, or the oral solution. The
total dose in each ofthese single treatments was Img EDDA + 501Jg EE . For the four
treatments, the mean plasma peak concentration of NET ranged from 6.5-8 .71Jg
alcohol solution. Peak blood NET concentrations were achieved within 4 h of
dosing with EDDA. The plasma NET concentrations decl ined in two ph ases, with
mean terminal elimination hal f-liv es of4.0-6.9 h.
An interesting comparison ofNET pharmacokinetics in women and adult female
rabbits and rhesus monkeys has been published by Prasad , Sivakumar & Narasinga
Rao (1979). Plasma level s ofNET were determined after administering either labelIed
NET or a NET mini-pill. Pharmacokinetic parameters were evaluated by using a
two -compartrnent open model and by graphical and regression ana lysis of plasma
NET data. In rabbits, the drug absorption was found to be rapid and NET peak levels
were attained within 0.5 to 1.0 h. The clearance half-l ives were 1.3 h for ' o : and
10.0 h for 'ß'. In monkeys, plasma NET values showed an inconsistent pattern and
On this basis, it would appear that th e rabbit is a suitabJe animal model for studying
effects ofnutritional factors on the pharmacokinetics ofNET.
A study of the pharmacokinetics of NEA in women has been reported by Singh ,
Uni yal, Jha, Murugesan , Takkar, Hingorani & Laumas (1979). Six previously
untreated healthy female volunteers aged 25-35 years rece ived a single intravenous
inje ct ion of tr iti ated NEA dissol ved in 10% alcoholic saline. Blood specimens were
collected at intervals up to 72 h, measurements made of total radioactive steroids,
conjugated steroids, and free steroid. The disappearance curve of NEA showed an
initial rapid disappearance with an average half-life of 7.5 min and a subsequent
slower disappearance with a half-life of 51.5 h. The average metabolic clearance rate
from the plasma ofNEA was 495 lit re da y" . Following intravenous injection , NEA is
rapidly metabolised to NET, wh ich then disappears from the plasma with an average
half-life of 34 .8 h. Unidentified tritiated metabolites persisted in the free steroid
fraction ofplasma in signi ficant amount s for as long as 72 h after the injection.
A radioimmunoassay is described by Saxena, Shrimanker & Fotherby (1977) for
measuring NEE directly in sampies of plasma after methanol prec ipitation. The
method ut ilises an antiserum produced against NEE-3-carboxymethylox ime coupled
to bovine serum albumin. The method is highly specific. Pla sma levels of the NEE
were from 1000-2500pg mi-I I week after inje ction dec reasing to 100-200pg mI-lover
the next 6 week s. The pattern ofNEE concentration s in pla sma was similar to that of
A number of totally synthetic progestogens in th e gonane ser ies have been used
commercially or experimentally as contraceptives. These include NG , used in sorne
countries as the equimolar mixture ofLNG and the dextro-rota ry enantiomer, but in
most piaces as LNG alone (the hormonall y active stereoisomer). Other gonanes
include the long-acting injectable, NG-pelargonate, and the orally active compounds
norgestimate (the 3-oxime of LNG-17-acetate), and ORG 3969 (lI-methylene-3-
It is ofconsiderable interest to know ifthe metabolism ofactive LNG is the same or
different to that of dextrorotary-NG. This problem has been investigated by
Sisenwine, Kimmel, Liu & Ruelius (1975) who have administered I.5mg of
14C-labelled compound (either (+)-, (-)-, or (± )-NG) to volunteer women . Mean
percentage recovery of radioactivities was as follows (in 7 da ys): LNG-urine 45 ,
faeces 32 ; (+)-NG-urine 64 , faeces 25 ; NG-urine 58 , faeces 23 . No significant
oestrogen formation was observed with metabolism of LNG, though minor
amounts of phenols were seen with (+)-NG. Other metabolic pathways ma y be
summarised as folIow s: LNG 2 a-hydroxylation, 3 a , 5 ß-reduction,
Using specific radioimmunoassays, Mishell, Kletzky, Brenner, Roy & Nicoloff
(1977) have measured seru m levels of NG at intervals after the ingestion of
various NG + EE tablets (0.5mg NG + 501Jg EE , 0.3mg NG + 501Jg EE, 0 .075mg
NG + 301Jg EE . Inhibition of ovulation appears to require a peak concentration in
serum of31Jg litre-' LNG (lO.Inmollitre-l
) and /or a minimum level of hg litre-! LNG
) when the oral contraceptive is taken orally once daily.
An interesting study by Nilsson, Victor & Nygren (1977) shows that the sex
hormone-binding globulin binds LNG in vivo. A minipill containing 301Jg LNG
was given to three women immediately following anormal del ivery, and to three
others who had had a legal abortion. All women had high concentrations of plasma
sex hormone-bind ing globulin and developed plasma concentration s of LNG 6 to 8
times higher than seen in women with normal sex hormone-binding globulin levels
receiving the same minipill. Continued adm inistration was accompanied by a fall in
plasma LNG until the sex hormone-binding globulin concentration dropped to the
usual range. Victor & Johansson (1977) noted reduced plasma SHBG concentration
in women treated with LNG (released from a vaginal ring), but normal values were
restored within three weeks when treatment was withdrawn. Oral administration of
LNG at dail y doses ofO .25mg, 0.5mg or 1.0mg resulted in a doubling ofplasma LNG
concentration on doubling ofthe oral do se. No such correlations between SHBG and
MPA were found in women receiving thi s progestogen .
Studies with tritiated LNG in lactating women are presented by Mützel & EI
Mahgoub (1977). Each of two mothers was given 301Jg of tritiated LNG on the third
da y post-partum and each of two mothers was given the same do se on the seventh,
ele venth and fifteenth da y po st-partum, while on the intervening da ys they recei ved
301Jg of unlabelled LNG. It is concluded that the extent of excretion of LNG and its
metabolites in breast 'm ilk is dependent from the time post-partum when this steroid
is taken. Plasma protein transport capacity and fat content and remaining
composition of the breast milk appear to play a part. Unchanged LNG dominates
quantatively in plasma and milk compared with its metabolites. Following the
administration of 301Jg LNG orally approximately 10-20ng LNG and metabolites
might be ab sorbed daily by the infant from breast milk. Amongst the metabolites
identified in milk are 16-hydroxy-3 a , 5ß-tetrahydro LNG, 6 ß-hydroxy LNG,
16ß-hydroxy LNG, together with a number of non polar compounds. The authors
po int out that quantities of steroids are a pproximately 100,000 sma ller than those
wh ich could be transferred to the in fant in the form of natural stero ids, such as
An interesting comparative pharmacokinetic study of three progestogens (LYN,
CPA, LNG) has been published by Humpel, Wendt, Schulze, Dogs, Weiss & Speck
(1977). The micronised compounds, labelIed with either 14C or JH, were administered
orally combined with 50~ EE to six women. A 14-day interval was allowed
between doses. Plasma progestogen concentration and total radioactivity were
recorded up to 5 and 8 da ys after ingestion. All progestogens were completely
absorbed at comparable rates. Postmaximum courses of disposition were
characterised by two phases, the first ofwhich had a half-life ofabo ut three hours and
was not substance specific. The half-life ofthe second phase was about the same for
LNG and CPA (1.5 and 1.7 h respectivel y), but was significantly higher for LYN
(2.5 h). Percentages of doses recovered in urine and faeces respectivel y were: LNG
48 ,46, LYN 50 , 39 , CPA 30 , 58 . There was a marked discrepancy between plasma
radioactivity and NET concentration following LYN. This was not due to
unconverted LYN and presumably related to some other metabolite.
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