Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13)
| Autor: | Darin DuMez, Fatih M. Uckun, Heather Tibbies, Douglas Erbeck, Taracad K. Venkatachalam |
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| Rok vydání: | 2007 |
| Předmět: |
Male
medicine.drug_class Metabolite Antineoplastic Agents Capsules Pharmacology Tyrosine-kinase inhibitor Excipients chemistry.chemical_compound Mice Dogs Pharmacokinetics Suspensions Oral administration Drug Discovery Nitriles Agammaglobulinaemia Tyrosine Kinase Bruton's tyrosine kinase Medicine Animals Tissue Distribution Chromatography High Pressure Liquid Mice Inbred BALB C Leukemia biology business.industry Protein-Tyrosine Kinases Amides Bioavailability Rats chemistry Intestinal Absorption Enzyme inhibitor Rats Inbred Lew Injections Intravenous biology.protein Gelatin Female business Tyrosine kinase |
| Zdroj: | Arzneimittel-Forschung. 57(1) |
| ISSN: | 0004-4172 |
| Popis: | The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%. LFM-A13 enters, but does not bind to multiple tissues followed by a rapid elimination from most of the tissues. Limited distribution of LFM-A13 to extravascular tissues and its corresponding low volume of distribution could be attributed to its plasma protein binding. LFM-A13 was not toxic to mice, rats, or dogs at daily dose levels as high as 100 mg/kg. LFM-A13 formulated as a suspension and hard gelatin capsules for oral administration showed a rapid absorption and favorable pharmacokinetic features. These preclinical research studies provide the basis for future pre-IND studies and clinicaldevelopment of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK. |
| Databáze: | OpenAIRE |
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