Introduction
Cetrorelix acetate (C70H92ClN17O14, referred to as cetrorelix), a synthetic decapeptide with 5 amino acids in the D-configuration, is a potent, pure competitive antagonist at the human gonadotrophin-releasing hormone (GnRH) receptor. It is an analog of native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, and 10. The molecular formula is acetyl-D-3-(2x-naphtyl)-alanine-D-4-chlorophenyalanine-D-3-(3x-pyridyl)-alanine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide. It has now been developed into a pharmaceutical dosage under the trade name Cetiotrde.
Biological Activity
Due to positive estradiol feedback at midcycle, GnRH liberation is enhanced, resulting in an LH surge, which induces the ovulation of the dominant follicle, resumption of oocyte meiosis, and subsequently luteinization as indicated by rising progesterone levels. In a dose-dependent manner, cetrorelix can compete with natural GnRH for binding to membrane receptors on pituitary cells and thus control the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It can be rapidly absorbed following subcutaneous injection with maximal plasma concentrations occurring 1-2 hours after administration. The mean absolute bioavailability of cetrorelix following subcutaneous administration to healthy female subjects is 85%.
Function
Cetrorelix is a potent antagonist of luteinizing hormone-releasing hormone (LH-RH) or GnRH. It has been shown in healthy human males that initial high loading dose injections followed by much lower daily doses of the GnRH antagonist are sufficient for effective suppression of LH, FSH, and testosterone. It is effective, well tolerated, and safe for the prevention of premature ovulation in women undergoing controlled ovarian stimulation. As an effective, longer acting, safer third-generation GnRH antagonist, Cetrorelix has an advantage over GnRH anonists, such as leuprolide acetate, because it can reduce the fertility therapy cycle to days rather than weeks. In addition to competitive receptor blockade, other mechanisms of antagonist action, such as receptor down-regulation, seem to be involved during long-term administration. Cetrorelix therefore appears to be suitable for therapy of sex-hormone dependent cancers, such as prostate carcinoma, and for the treatment of infertility.
References:
1. R. Lizio, et al. Systemic delivery of the GnRH antagonist cetrorelix by intratrachealinstillation in anesthetized rats. European Journal of Pharmaceutical Sciences, 2000, 9, 253-258.
2. Katharina Erb, M.D., et al. Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women. FERTILITY AND STERILITY, 2001, 75(2), 316-322.
3. Ho, Rodney J. Y., and M. Gibaldi. Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs. Biotechnology and Biopharmaceuticals. 2013, 125-136.
