Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent…
Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels.
Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL
- A. Kamath, Jian Wang, F. Lee, P. Marathe
- Biology, MedicineCancer Chemotherapy and Pharmacology
- 1 March 2008
Dasatinib shows intermediate clearance in mouse, rat, dog, and monkey, and distributes extensively in those species, and Oxidative metabolism appears to be the predominant clearance pathway.
Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition
- Y. Lai, S. Mandlekar, P. Marathe
- Biology, MedicineJournal of Pharmacology and Experimental…
- 1 September 2016
It is concluded that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OatP drug-drug interaction liabilities in early clinical studies.
Cynomolgus Monkey as a Potential Model to Assess Drug Interactions Involving Hepatic Organic Anion Transporting Polypeptides: In Vitro, In Vivo, and In Vitro-to-In Vivo Extrapolation
- Hong Shen, Zheng Yang, A. D. Rodrigues
- Biology, ChemistryJournal of Pharmacology and Experimental…
- 1 March 2013
The cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting and a number of in vitro–in vivo extrapolation approaches were explored.
PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling…
The PBPK approach based on in vitro-input data was as accurate as the approachbased on in vivo data and the implications of compound properties are demonstrated.
Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression
The findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of Creatinine.
PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution.
Evaluated methodologies for the prediction of human volume of distribution at steady state with and without protein binding corrections found the top three methods that perform strongly at integrating in vivo data in this way were the Øie-Tozer, the rat -dog-human proportionality equation, and the lumped-PBPK approach.
Selective Itk inhibitors block T-cell activation and murine lung inflammation.
These findings represent the first description of selective inhibitors to probe human Itk function and its associated pathway, and support the hypothesis that Itk is a therapeutic target for immunosuppressive and inflammatory diseases.
Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species
It is concluded that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.
Comparative Evaluation of Plasma Bile Acids, Dehydroepiandrosterone Sulfate, Hexadecanedioate, and Tetradecanedioate with Coproporphyrins I and III as Markers of OATP Inhibition in Healthy Subjects
Investigation of bile acids and fatty acid dicarboxylates in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs confirmed that CPs are novel biomarkers suitable for clinical use.