CLINICAL PHARMACOLOGY
ORAL CONTRACEPTION
Combination oral contraceptives act by suppression of
gonadotropins. Although the primary mechanism of this
action is inhibition of ovulation, other alterations include
changes in the cervical mucus (which increase the difficulty
of sperm entry into the uterus) and the endometrium (which
reduce the likelihood of implantation).
Receptor binding studies, as well as studies in animals
and humans, have shown that norgestimate and 17-deacetyl
norgestimate, the major serum metabolite, combine high
progestational activity with minimal intrinsic androgenicity.90-93
Norgestimate, in combination with ethinyl estradiol, does
not counteract the estrogen-induced increases in sex hormone
binding globulin (SHBG), resulting in lower serum testosterone.90,91,94
ACNE
Acne is a skin condition with a multifactorial etiology.
The combination of ethinyl estradiol and norgestimate
may increase sex hormone binding globulin (SHBG) and decrease
free testosterone resulting in a decrease in the severity
of facial acne in otherwise healthy women with this skin
condition.
Norgestimate and ethinyl estradiol are well absorbed
following oral administration of ORTHO-CYCLEN and ORTHO
TRI-CYCLEN. On the average, peak serum concentrations
of norgestimate and ethinyl estradiol are observed within
two hours (0.5-2.0 hr for norgestimate and 0.75-3.0 hr
for ethinyl estradiol) after administration followed by
a rapid decline due to distribution and elimination. Although
norgestimate serum concentrations following single or
multiple dosing were generally below assay detection within
5 hours, a major norgestimate serum metabolite, 17-deacetyl
norgestimate, (which exhibits a serum half-life ranging
from 12 to 30 hours) appears rapidly in serum with concentrations
greatly exceeding that of norgestimate. The 17-deacetylated
metabolite is pharmacologically active and the pharmacologic
profile is similar to that of norgestimate. The elimination
half-life of ethinyl estradiol ranged from approximately
6 to 14 hours.
Both norgestimate and ethinyl estradiol are extensively
metabolized and eliminated by renal and fecal pathways.
Following administration of 14C-norgestimate, 47% (45-49%)
and 37% (16-49%) of the administered radioactivity was
eliminated in the urine and feces, respectively. Unchanged
norgestimate was not detected in the urine. In addition
to 17-deacetyl norgestimate, a number of metabolites of
norgestimate have been identified in human urine following
administration of radiolabeled norgestimate. These include
18,19-Dinor-17-pregn-4-en-20-yn-3- one, 17-hydroxy-13-ethyl,(
17a )-(-); 18,19-Dinor-5b -17-pregnan-20-yn, 3a , 17b
-dihydroxy-13-ethyl,( 17a ), various hydroxylated metabolites
and conjugates of these metabolites. Ethinyl estradiol
is metabolized to various hydroxylated products and their
glucuronide and sulfate conjugates.
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