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CLINICAL PHARMACOLOGY

Pharmacodynamics

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 changes in the endometrium which reduce the likelihood of implantation.

Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.

In the third cycle of use after a single desogestrel and ethinyl estradiol tablet, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean±SD) are reached at 1.4±0.8 hours. The area under the curve (AUC0-∞) is 33,858±11,043 pg/mL · hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840±1,667 pg/mL are reached at 1.4±0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400±560 pg/mL. The AUC0-24 at steady state is 52,299±17,878 pg/mL · hr. The mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150±64 nmol/L) to day 21 (230±59 nmol/L). The elimination half-life for 3-keto-desogestrel is approximately 38±20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3a-OH-desogestrel, 3ß-OH-desogestrel, and 3a-OH-5a-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides.

Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single desogestrel and ethinyl estradiol tablet, the relative bioavailability is approximately 83%.

In the third cycle of use after a single desogestrel and ethinyl estradiol tablet, maximum concentrations of ethinyl estradiol of 95±34 pg/mL are reached at 1.5±0.8 hours. The AUC0-∞ is 1,471±268 pg/mL · hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141±48 pg/mL are reached at about 1.4±0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24±8.3 pg/mL. The AUC0-24, at steady state is 1,117±302 pg/mL · hr. The mean AUC0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.

The elimination half-life is 26±6.8 hours at steady state. Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

REFERENCES:

91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of progestogens used in oral contraception. Contraception 1988;38:325-32. 92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim. Forsch/Drug Res, 1983; 33(I),2:231-6.

Last reviewed on RxList: 3/19/2008
This monograph has been modified to include the generic and brand name in many instances.

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