Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours
| Autor: | Nakpangi Johnson, Håkan Andersson, Terri Mitchard, Eike Floettmann |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Time Factors medicine.drug_class Narcotic Antagonists (+)-Naloxone Pharmacology Biology Toxicology Risk Assessment Polyethylene Glycols Capillary Permeability Rats Sprague-Dawley Mice 03 medical and health sciences Naloxegol chemistry.chemical_compound Dogs Species Specificity Testicular Neoplasms Internal medicine Toxicity Tests medicine Animals Humans Testosterone Leydig cell Luteinizing Hormone Methylnaltrexone Naltrexone Up-Regulation Quaternary Ammonium Compounds 030104 developmental biology Endocrinology medicine.anatomical_structure Morphinans Opioid chemistry Blood-Brain Barrier Female Rabbits Luteinizing hormone Biomarkers Opioid antagonist Leydig Cell Tumor medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 329:85-95 |
| ISSN: | 0041-008X |
| Popis: | Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant. |
| Databáze: | OpenAIRE |
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