A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Ortho Tricyclen Pharmacology, Pharmacokinetics, Studies, Metabolism - Norgestimate and Ethinyl Estradiol
Ortho Tricyclen Pharmacology, Pharmacokinetics, Studies, Metabolism - Norgestimate and Ethinyl Estradiol
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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