Pharmacokinetics of desogestrel

Abstract

A synthetic form of desogestrel, a gonane progestin, was developed because desogestrel's enhanced selectivity eliminates adverse, androgen-dependent, metabolic effects at contraceptive doses. Desogestrel is rapidly and completely metabolized in the liver and gut wall to 3-keto-desogestrel, which is the active metabolite mediating the progestin effects. Because of its unique 11-methylene side chain, desogestrel cannot be metabolized to any other known progestin, nor is desogestrel a naturally occurring metabolite of any other progestin. The pharmacokinetic parameters of 3-keto-desogestrel are generally comparable with those of levonorgestrel and norethindrone. Therefore any differences in pharmacologic activities must be attributed to differences in intrinsic activities. Unlike gestodene, 3-keto-desogestrel has a lower affinity for sex hormone-binding globulin, which results in markedly lower plasma levels after administration. After oral administration of 150 micrograms of desogestrel, plasma levels are less than half the levels of gestodene after an oral dose of 75 micrograms.

PIP: A synthetic form of desogestrel, a gonane progestin, was developed because desogestrel's enhanced selectivity eliminates adverse, androgen-dependent, metabolic effects at contraceptive doses. Desogestrel is rapidly and completely metabolized in the liver and gut wall to 3-keto-desogestrel, which is the active metabolite mediating the progestin effects and is considered exclusively responsible for desogestrel's pharmacologic actions. Hydroxylation at C3 in the intestinal mucosa and during first pass metabolism in the liver is responsible for the biotransformation. Its unique 11-methylene side chain assures that desogestrel cannot be metabolized to any other known progestin, nor is desogestrel a naturally occurring metabolite of any other progestin. The pharmacokinetic parameters of 3-keto-desogestrel are generally comparable with those of levonorgestrel and norethindrone. Unlike gestodene, 3-keto-desogestrel has a lower affinity for sex hormone binding globulin (SHBG), which results in markedly lower plasma levels after administration. After oral administration of 150 mcg of desogestrel, plasma levels are less than half the levels of gestodene after an oral dose of 75 mcg. Comparable pharmacokinetics were observed after the oral administration of identical doses of 3-keto-desogestrel and desogestrel, with the exception of serum levels 30 minutes after drug administration. Bioavailability of 3-keto-desogestrel averages 76.1% after the oral administration of desogestrel and ethinyl estradiol (EE). Desogestrel, in combination with EE, causes an increase in SHBG to the same extent as does estrogen alone and is associated with the lowering of free testosterone. Therefore, it is thought to be generally devoid of androgenic effects probably caused by an increase in serum SHBG as well as by a possible decrease in ovarian testosterone production. Thus, the pharmacokinetic characteristics of desogestrel make it a suitable candidate for use in OCs.