Pharmacokinetics and metabolism of lhrh agonists, clinical aspects

Abstract

The authors investigated the pharmacokinetic measurement methods for determination of the the highly active luteinizing hormone-releasing hormone (LHRH) agonist buserelin in animal plasma and serum with emphasis on the detection of intact peptide and metabolities. These methods were applied to the study of endometriosis prostate cancer and precocoious puberty and to the monitoring of use of a buserelin nasal spray as a contraceptive. Even after a small nasal spray dose (400 mcg) the biologic effect of buserelin on LH release was striking and unequivocal. Although the plasma LH increase was measured for over 6 hours the plasma level of buserelin was only transiently elevated. Both the acute LH release and the urinary excretion of immunoreactive buserelin appear to be the most reliable pharmacokinetic parameters during low-dose stimulation. The utility of buserelin determination in unextracted urine was confirmed by application of the method to dose-finding studies. Parameters used for calculations is studies on urinary excretion of immunoreactive buserelin after nasal spray administration included urinary buserelin excretion buserelin plasma level and the LH release induced. Due to the high doses used in pituitary-gonadal suppression by LHRH agonists as well as the sustained levels observed during high-dose injection and longterm infusion therapy the risk of antibody formation must be evaluated carefully. No formation of antibodies was detected in any of the clinical studies. This low antigenic potential is considered a result of the small moelecular size of LHRH agonists and the rapid rate of degradation by exo- and endopeptidases. In general determination of urinary excretion is the preferred method for therapy control although determination of plasma levels can be performed for rapid evaluation or additional confirmation.