Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL.

Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Research Abstract Details 

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Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Abstract Text:

Amrita V Kamath,Jian Wang,Francis Y Lee,Punit H Marathe,Amrita V Kamath,Jian Wang,Francis Y Lee,Punit H Marathe,

PURPOSE: Dasatinib (BMS-354825), a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL, has recently been approved for the treatment of chronic myelogenous leukaemia (CML) in imatinib-acquired resistance and intolerance. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism of dasatinib in mouse, rat, dog, and monkey. Possible mechanisms contributing to the incomplete oral bioavailability of dasatinib in animals were investigated. METHODS: Metabolic stability of dasatinib was measured after incubation with liver microsomes (either NADPH- or UDPGA-fortified) and isolated hepatocytes obtained from mouse, rat, dog, monkey, and human. In all cases, substrate depletion over time was measured, and appropriate scaling factors were used to predict in vivo clearance. Pharmacokinetics of dasatinib were determined in mice, rats, dogs, and monkeys after administration of single intravenous or oral doses. In addition, the routes of excretion were investigated after administration of dasatinib to bile duct cannulated (BDC) rats. Absorption and first-pass metabolism were evaluated as possible reasons for the incomplete oral bioavailability using various in vitro and in vivo models like Caco-2 cells, P-glycoprotein (P-gp) knockout mice, and intra-portal dosing in rats. RESULTS: In vivo systemic plasma clearance values of dasatinib were 62, 26, 25, and 34 ml/min/kg in mouse, rat, dog, and monkey, respectively. Scaling of in vitro hepatocyte and liver microsomal data gave reasonably good predictions of in vivo clearances across all species. Percent distribution in blood cells ranged from 43% in mouse to 57% in dog. Dasatinib showed high volumes of distribution (>3 l/kg) and high serum protein binding values (>90%) in all four species tested. Oral bioavailability of dasatinib ranged from 14% in the mouse to 34% in the dog. In rats, bioavailability after an intraportal dose was comparable to that after intra-arterial administration. In BDC rats, less than 15% of an intravenous dose was excreted unchanged in urine, bile, and the gastrointestinal tract, suggesting that dasatinib is cleared primarily via metabolism. Dasatinib has high intrinsic permeability in Caco-2 cells, however, the efflux ratio was approximately two-fold indicating that it may be a substrate for an intestinal efflux transporter. However, in vivo studies in P-gp knockout mice versus wild-type mice showed no difference in the amount of dasatinib remaining unabsorbed in the gastrointestinal tract, suggesting that P-gp may not be responsible for the incomplete bioavailability. CONCLUSIONS: Dasatinib shows intermediate clearance in mouse, rat, dog, and monkey, and distributes extensively in those species. Oxidative metabolism appears to be the predominant clearance pathway. The incomplete oral bioavailability may be due to both incomplete absorption and high first-pass metabolism. However, the efflux transporter, P-glycoprotein does not appear to be limiting oral absorption.

Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Publishing Authors By Initials

AV Kamath,J Wang,FY Lee,PH Marathe,AV Kamath,J Wang,FY Lee,PH Marathe,

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Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Cancer chemotherapy and pharmacology

VOLUME: 61

Page Numbers: 365-76

Journal Abbreviation: Cancer Chemother. Pharmacol.

ISSN: 0344-5704

DAY: 11

MONTH: 04

YEAR: 2007

Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Information

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LANGUAGE: eng

NlmUniqueID: 7806519

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AFFILIATION: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.

Country: Germany

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MEDLINETA: Cancer Chemother Pharmacol

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