Metabolism of NG by the female baboon has been investigated by Sisenwine,
primates, including 3 a , 5 ß -tetrahydro NG, 2 a-hydroxy NG, 16ß hydroxy NG, and
l3-ethyl-D-homogon-4-ene-3 , 17 a-dione wer e detected in both unconjugated and
conjugated fractions. The sulp hated metabolites ofNG detected in human urine were
not evident, and the 3 a , 5ßtetra hydro NG was the major metabolite in one baboon.
A comparison ofresults in the baboon with those seen in African green monkeys and
in women suggest that the baboon is not a good model for NG metabolism, and that
the metabolite pattern seen in the green monkey is closer to that in th e wornan, where
16 ß-NG (as sulphate) appears to constitute about one-third of the total urinary
ac tivity following orallabelled-NG (Sisenwine et al., 1978).
Sisenwine, Liu, Kimmel & Ruelius (1977) used ['4C)-norgestimate in rhesus
monkeys, given as a single intragastric do se (0.5mg kg-I
into blood and two major metabolites were detected (LNG and LNG-3-oxime). The
authors suggest that norgestimate is rapidl y converted to LNG-3-oxim e, which is
then more slowly converted to LNG. The principal metabolite of th e latter is
probably a glucuronide conj ugate ofl3 ß-ethyl-17 a-ethyn yl-5 ß-gona-3 a , 17ß-diol.
The human pharmacokinetics ofnorgestimate (the 3-oxime of LN G -17-aceta te) in
the pre sence and absence of EE ha s been studi ed by We intraub, Abrams, Patrick &
McGuire (1978 ). ln vestig at ions were made on seven healthy women who received a
single capsule of 14C-labelled norgestim at e either alone or in combination with
(lH]-EE. The do se ofnorgestimate was 0.49 or 0.50mg, while the EE do se was 140~
da y prior to administration and then all urine and faece s were collected for 2 week s
thereafter. Plasma radioacti vity peak s due to both 14C and JH occurred in plasma
within 2 h after drug administration, to be followed by distribution and elim ination
phases. The half-life of plasma [14C)-norgestimate had a mean value of 59 .5 h with a
range of 45-71 h. When administered with EE , the half-life of norgestimate was
elimination of 14C following oral [14C)-norgestimate over the 2-week collection period
was 83 .5% with a range of 64-94%. Urinary radioactivity accounted for a mean
46 .8%, while a mean 36 .8% was recovered in the faece s. The adm inistra tion in
combination with EE appeared to ha ve little etTect on the routes or amounts of
(c) l Zu Acetoxyp rogestero nes
The principal compounds in thi s, in terms of actual or experimenta l use, are MPA,
MGA, CMA, CPA and melengestrol acetate. MPA and CMA ha ve found use both as
oral and injectable contraceptives, wh ile MGA has been used in oral contraception
and implants. Rev iews on the metabolism ofthese compounds ha ve been published
by Fotherby & James (1972) and Fotherby (1974). They have somewhat fallen from
favour due to their increased tendency to induce mammary lesions in chronic
toxicity tests in high doses with beagle dogs (Owen & Briggs, 1975). The relevance of
these findings to safety in human use is highly questionable (Briggs, 1980).
Much of the label from progestogens in this group is excreted primarily via the
urine in primates, though the dog favours biliary (and faecal) excretion (Hili, 1972).
Slaunwhite & Sandberg (1961) recovered in humans up to 42% of label from i.v,
[14C)-MPA in urine compared with up to 13% in faeces. The biological half-life
appeared to be about 14.5 h (about half that of NET). Similarly for labelled-MGA,
Cooper & Kellie (1968) recovered up to 78% in urine and up to 30% in faeces. The
values for CMA were up to 43% in urine and up to 28% faeces (Dorfman, 1971).
Hydroxylation ofthe 17-acetoxyprogestogens occurs at C-6 with MPA (Helmreich
& Huseby 1962; Castegnaro & Sala, 1962), MGA (Cooper & Kellie, 1968), and
melengestrol acetate (Cooper, Elce & Kellie, 1967) and at C-21 with MPA (Helmreich
Martin & Adlercreutz (1977) discusssome aspects ofMGA and MPA metabolism.
Using radioimmunological and mass fragmentographic methods, they have
measured the concentration of these two progestogens in human plasma following
oral administration. Oral administration of the same doses leads to much higher
plasma concentration ofMGA than MPA. Metabolites ofMGA in human bile were
almost exc1usively glucuronide conjugated, whereas in urine both sulphate and
glucuronide conjugated metabolites were found . Monohydroxylated metabolites
predominated, though evidence ofMGA reduction was also apparent. An interesting
comparative experiment in the beagle dog was also conducted. Metabolites in female
and male dogs were investigated by the same procedure and the female showed
metabolites similar to those found in humans for the liver. One metabolite was
detected in the male in the glucuronide fraction from bile and appeared to be unique
A comparison of CMA metabolism in the rat, rabbit, dog and human is discussed
by Honma, Iwamura, Iizuka, Kambegawa & Shida (1977). Fourteen unconjugated
metabolites and three conjugated metabolites were isolated from urine , faeces and
bile following oral administration. Structures ofthe metabolites were deduced. Again
a marked species difference in metabolic pattern was established. The major urinary
metabolite in man was the 2-hydroxy CMA, with significant amounts of 3-hydroxy
and 5ß-metabolites. The occurrence of I-hydroxylation and 5-hydroxylation
reactions, which are new metabolic pathways, is described in both the rat and
human. Anti-androgenie activities of the various metabolites are listed. One of the
main metabolites in humans and rats is 3ß-hydroxy CMA. This compound and its
acetate was 0.7 times as active as CMA an an anti-androgen . Most other metabolites
were ineffective in this assay. A summary ofresults is given in Tables 3 and 4.
Humpel, Wendt, Dogs, Weib, Rietz & Speck (1977) have studied the biovailability
and pharmacokinetics ofa new oral contraceptive (2mg CPA + 501Jg EE). Single oral
Table3 Chlormadinone acetate (CMA)metabolites(1)*
Mean %totalradioactivity infaeces
do ses were adm inis te red to six healthy wo me n. CPA was lab ell ed with 14C, while EE
was lab elled with JH . Elimi na tio n of labelled material in urine and faeees was
measured for th e next 10 days , whi le the amount of 14C in plasma, together with
radioi m m unoassaya ble C PA, was measured for 5 da ys. T he maximum plasm a
eo neent ra tion of C PA oeeurred at 4 h post-admin ist rat ion (7.2 ± IAIJ8 litre'";
Table4 Chlormadinone acetate (CMA) metabolites (11)*
Metabolite Mean %total radioactivitv in bile
The metab olie fat e of MA P was studied in intaet baboon s and in tho se with bile
do se was reeovered in th e urine in 7 h in intaet baboons, as weil as in th e urine of
baboons with biliary fistulas. Higher amo unts of radioaetivity were exereted in th e
bile (approximate ly 25 %), amounting to almost double the pe rcentage exereted in th e
urine. T he similarity in the uri nary exe re tion of radioaetivity in intaet and biliary
fistula animals indieates t hat, even though a substa ntia l b ilia ry exe retion of th e
labelled MAP occurred, th e amount involved in an enterohepatie eireulation is
probably sma ll. Glueurona tes were the predom inent conj ugates, both in the urine
a nd bile. T he loss of th e 17a-aeetate gro up appeared to be rather extensive, ra ngi ng
from 30 to 70%. among different eonj ugated and un eonjugated metabolites of MA P.
The deaeet ylat ion ofthe 17 (I-acetate in MA P was simi lar to th at ob se rved in human s
give n th e dr ug. Oxygenation of MA P at positions I and /or 2 a ppeared to m in im al
The teehnique for det erm ining th e eo m pa ra tive meta bol ism of pro gestogen s has
been eva lua ted by Gupta, Ma thur & Garg (1 977) . Usi ng 14C and JH labelIed MPA th e
mat eri al was ad m inis te red to four different species, inclu d ing seven wornen, six
mon keys, seve n dogs a nd six rats. The metaboli e c1 earan ee ra te. ex pressed in litres
day'" kg-1 varied from a mean of 2 \ in women to 45 in dogs . The a utho rs eomment
that th e between spe eies va riations in c1earanee rate for M PA a ppears to be less th an
A wa rni ng on eval ua ting results from studies using a single injeetion teehnique of
the metabol ism ofsynthetie pr ogestogen s suc h as MPA in wo me n has been published
by G upta. Osterma n. Sante n & Bardin (1979) . Cornputer-irnp leme nted ana lysis was
used to ealc ulate the MCR and vo lume of distribution fro m the steroid d isappearanee
eurve. T he effee t of prot oeol de sign (number a nd freque ne y of sam pIes) on th ese
metabol ie pa ra me ters wa s eva luated. The esti matio n of VoMPA was most sensitive to
a lterations of ex pe riment a l de sign an d biologieal va riability, whi le MC T was less
eas ily effeeted. T he MCR MPA of 1668 ± 146 litres 24 h-1 was lower tha n that for
progesterone but higher th a n that of another sy nthetie steroid , dexamethasone .
Treatment ofwomen wit h MPA or a m in og lu teth im ide, two drugs known to increase
the rates of testosterone and dex amethasone metabolism, respecti vel y, did not alter
MCR MPA. lt is concluded that with the si ng le inj ec ti o n te chn ique it is difficult to
est imate Vo of compounds suc h as MPA which a re rapidl y metabolized a nd th at the
MCR MPA was higher than ex pec ted a nd less susceptible to drug-induced changes than
the c1earance o f other steroids .
A rec ent evaluation by Fotherby et al. (1979) is o f pa rt icular interest
for this gro up of co m po unds, wh ich m a y find eventua l use prim arily as long-acting
depot co ntraceptives . The duration ofaction oflong-acting inject abl e formulations of
progestogens wa s assessed in rabbits b y m ea suring blood level s o f the compounds.
NEE wa s ra p id ly absorbed and metabolised and NET was detect able in pl asma for
up to 60 to 70 days. After admin istration of MPA pl asma level s were detectab!e fo r
up to 110 days and a fter injection of NG-pelargonate, NG wa s detected in plasma fo r
a si m ila r period oftime. ORG 2154(l6a-ethyl-21-h ydroxy-19-norprogesterone) wa s
slowl y metabolised and plasma levels o fthe free compound were detectable for more
than 180 da ys. The order o f duration of activity is compared with results obtained in
baboons and humans. The rabbit ma y se rve as a su itab le ani ma l model for predicting
the duration ofaction ofinjectable formulations in humans.
sex horm one-b inding globulin
Abdel-Aziz, M. T. & Will iam s, K. I. H. (1969). Metabolism of 17a -eth ynylestrad iol and its
3-methyl ether by the rabbit: an in vivo D-homoannulation. Steroids, 13, 809-820.
Abdel-Aziz, M. T. & William s, K.1. H. (1 970). Metabolism of radioactive 17a-ethynylestradiol
by women. Steroids. Ts, 695-710 .
Appe1gren, I. E. & Karisson , R. (1971). The distribution of [!4c]-4-mestranol in mice. Acta
Arai, K., Golab, T ., Layne, D. S. & Pincus, G. (1962). Metabolie fate of orall y administered
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