التفاصيل البيبلوغرافية
| العنوان: |
Pharmacokinetics of SB-247083, a potent and selective endothelin(A) receptor antagonist, in the rat, dog, and monkey |
| المؤلفون: |
Pamela R. Souder, Cherng-Yih Perng, Keith W. Ward, Michael J. Gould, Jayme A. Morgan, Brian R. Smith, Leonard M. Azzarano, David Lundberg |
| المصدر: |
Biopharmaceuticsdrug disposition. 23(8) |
| سنة النشر: |
2002 |
| مصطلحات موضوعية: |
medicine.hormone, Endothelin Receptor Antagonists, Male, medicine.medical_specialty, medicine.drug_class, Drug Evaluation, Preclinical, Pharmaceutical Science, Pharmacology, Endothelins, Dogs, Pharmacokinetics, Oral administration, Internal medicine, medicine, Animals, Pharmacology (medical), Receptor, Benzofurans, business.industry, Receptors, Endothelin, Antagonist, General Medicine, Receptor antagonist, Receptor, Endothelin A, Bioavailability, Rats, Macaca fascicularis, Endocrinology, Propionates, Endothelin receptor, business |
| الوصف: |
The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development. Copyright © 2002 John Wiley & Sons, Ltd. |
| تدمد: |
0142-2782 |
| URL الوصول: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c0ee13302ca8a767af9f8cef3e83289a
https://pubmed.ncbi.nlm.nih.gov/12415574 |
| حقوق: |
CLOSED |
| رقم الأكسشن: |
edsair.doi.dedup.....c0ee13302ca8a767af9f8cef3e83289a |
| قاعدة البيانات: |
OpenAIRE |
