Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites

https://doi.org/10.1016/0002-9378(90)90552-IGet rights and content

Abstract

Biotransformation, pharmacologic, and pharmacokinetic studies of norgestimate and its metabolites indicate that 17-deacetyl norgestimate, along with the parent drug, contributes to the biologic response. The postulated metabolic pathway, which is based on the identification of urinary products had indicated that three metabolites of norgestimate, 17-deacetyl norgestimate, 3-keto norgestimate, and levonorgestrel, might participate in the response. The pharmacologic evaluation of these metabolites demonstrates that only 17-deacetyl norgestimate has a pharmacologic profile consistent with that of norgestimate, and significant concentrations of this metabolite have been measured in the serum of women after the administration of norgestimate. These studies indicate that 17-deacetyl norgestimate contributes to the pharmacologic response to norgestimate.

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    Interestingly, 5α-NET is more potent via PR-A than PR-B, while 3α,5α-NET is a partial agonist for PR-B but not PR-A (Larrea et al., 2001). NGM is metabolized to LNG-17-acetate and NGMN, also known as 17-deacetyl-noregestimate or LNG-3-oxime (Juchem et al., 1993; McGuire et al., 1990), with NGMN being the main progestogenic metabolite (Fig. 2, Table 1). Both NGM and NGMN elicit progestogenic and androgenic activity (Juchem et al., 1993; Phillips, Demarest, Hahn, Wong, & McGuire, 1990; Prifti, Lelle, Strowitzki, & Rabe, 2004).

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    NGM is rapidly metabolized to 17-Desacetyl norgestimate (DNGM) and norgestrel (NG). DNGM is pharmacologically active and the pharmacologic profile is similar to that of NGM [3–6]. Given the rapid metabolism of NGM, the circulating concentrations of NGM are extremely low, which was one of the major challenges to quantify NGM in plasma or serum.

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    As the norgestimate serum concentrations following single or multiple dosing are generally below assay detection within 5 h, a major norgestimate serum metabolite, 17-desacetyl norgestimate (which exhibits a serum half-life ranging from 12 and 30 h), appears rapidly in serum with concentrations greatly exceeding that of norgestimate. The 17-deacetylated metabolite (pka 12.22) is pharmacologically active and the pharmacologic profile is similar to that of norgestimate [10–14]. Reported literature has mentioned, to assess the effect of anticonvulsants [8] and rosuavastatin [10], the pharmacokinetics of 17-desacetyl norgestimate and plasma was analyzed for 17-desacetyl norgestimate with validated LC–MS/MS method, but analytical method details are not available for monitoring plasma levels.

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