Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties.

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Hammond GL, Abrams LS, Creasy GW, Natarajan J, Allen JG, Siiteri PK

Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties.

Contraception. 2003 Feb;67(2):93-9.

PubMed ID

12586319 [ View in PubMed

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Abstract

Norelgestromin (NGMN) and levonorgestrel (LNG) are the main active metabolites of norgestimate (NGM), but their relative contributions to the pharmacological effects of NGM are unclear. We have therefore determined the serum distribution of these NGM metabolites and assessed their steady-state concentrations in women following >or=3 cycles of oral contraceptive (OC) use. The administration of 250 microg NGM/35 microg ethinyl estradiol (EE) resulted in significantly higher sex hormone-binding globulin (SHBG) levels (p = 0.002), and 30% lower serum non-protein-bound (NPB) levels of testosterone, when compared to treatment with 150 microg LNG/30 microg EE. We also confirmed that NGMN does not bind to SHBG, and found that 97.2% of this metabolite is bound to albumin while only 2.8% is in the NPB fraction. In contrast, most of the LNG was bound to SHBG (92.5% and 87.2% after NGM/EE and LNG/EE treatment, respectively), and the NPB fraction of LNG (0.7%) during NGM/EE treatment was lower (p < 0.001) than during LNG/EE treatment (1.4%). Combining these serum distributions with the C(max) and AUC(0-24h) data obtained after NGM/EE treatment gave NPB and albumin-bound values of NGMN that were much greater than the corresponding LNG values. Furthermore, the C(max) and AUC(0-24h) values for NPB LNG during NGM/EE treatment were estimated to be lower than during LNG/EE treatment. Since LNG is primarily bound by SHBG, its access to target tissues is restricted. Moreover, because SHBG does not bind NGMN, it appears to be quantitatively the more important NGM metabolite available to target tissues, and probably accounts for a substantial proportion of the progestogenic activity of NGM/EE OCs. However, it is also possible that simultaneous exposure of NGMN and LNG after treatment with NGM/EE may provide clinical benefits not seen with LNG/EE combinations.

DrugBank Data that Cites this Article

Drugs

Norgestimate

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Levonorgestrel	Sex hormone-binding globulin	Protein	Humans	Unknown	Inhibitor Binder	Details
Norelgestromin	Serum albumin	Protein	Humans	Unknown	Not Available	Details

Drug Carriers

Drug	Carrier	Kind	Organism	Pharmacological Action	Actions
Norgestimate	Serum albumin	Protein	Humans	Unknown	Binder	Details
Norgestimate	Sex hormone-binding globulin	Protein	Humans	Unknown	Binder	Details