Gonadotropin-releasing hormone (GnRH) analogs: relationship between their structure, proteolytic inactivation and pharmacokinetics in rats
| Autor: | Ingo Baeger, Hartmut Berger, Uwe Kertscher, Erika Albrecht, Michael Bienert, Nadja Heinrich, Johannes Oehlke, Burkhard Mehlis, Heinz Schäfer |
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| Rok vydání: | 1991 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Physiology Proteolysis Molecular Sequence Data Clinical Biochemistry Peptide Gonadotropin-releasing hormone Biology Kidney Biochemistry Gonadotropin-Releasing Hormone Structure-Activity Relationship Cellular and Molecular Neuroscience Endocrinology Pharmacokinetics Internal medicine medicine Animals Amino Acid Sequence Receptor chemistry.chemical_classification Membranes medicine.diagnostic_test Rats Inbred Strains Rats Amino acid Enzyme Activation medicine.anatomical_structure Liver chemistry Female Peptides hormones hormone substitutes and hormone antagonists Peptide Hydrolases Hormone |
| Zdroj: | Regulatory Peptides. 33:299-311 |
| ISSN: | 0167-0115 |
| DOI: | 10.1016/0167-0115(91)90232-6 |
| Popis: | There are two types of superactive agonists of gonadotropin-releasing hormone (GnRHa-I: ( d -amino acid)6-GnRH and GnRHa-II: ( d -amino acid)6-(desGly)10-GnRH-ethylamide) the high hormonal activity of which is understood to be due to their higher receptor affinity and their higher proteolytic stability as compared with the native GnRH sequence. Using the soluble fractions of various rat tissues in studies on the inactivation of GnRH peptides, we confirmed the higher proteolytic resistance of GnRHa-II, but not of d -Phe6-GnRH (GnRHa-I) and of another analog, d -Trp3- d -Phe6-GnRH, as compared with GnRH. The exact behaviour of the peptides during degradation was found to be dependent on the peptide concentrations used, showing the importance of using conditions as near to the physiological ones as possible. Towards the membrane fractions, however, the order of degradability was found to be GnRH ⪢ d -Phe 6 -GnRH ⪢ d -Trp 3 - d -Phe 6 -GnRH . The pharmacokinetic consequences of the different proteolytic degradabilities of the GnRH peptides, observed in rats, were a moderate increase in the biological half-life of d -Phe6-GnRH by 2.5-fold, as compared with GnRH, and a small increase in half-life of d -Trp3- d -Phe6-GnRH by 1.4-fold when compared with d -Phe6-GnRH. Whereas no intact GnRH was recovered in rat urine, small amounts of d -Phe6-GnRH (about 1% of dose) and high amounts of d -Trp3- d -Phe6-GnRH (25.5%) were excreted into urine. Combining the biochemical and pharmacokinetic data, it is concluded that proteolytic stability of GnRH analogs in pharmacological terms means stability towards membrane enzymes (pharmacologically-related stability) and that designing analogs with further increased proteolytic stability will be of only limited consequences with respect to their biological half-lives, the glomerular filtration rate of the kidney becoming the determining factor in the peptide clearance. |
| Databáze: | OpenAIRE |
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