SPRYCEL (dasatinib; Bristol-Myers Squibb, Princeton, NJ) is a multiple kinase inhibitor that potently inhibits Bcr-Abl, Src family (Src, Lck, Yes, Fyn), c-Kit, EPHA2, and platelet-derived growth factor receptor  kinases (Lombardo et al., 2004;Shah et al., 2004;Das et al., 2006). It is currently approved in the United States and European Union to treat chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec, Novartis, Basel, Switzerland). Unlike imatinib mesylate, which binds to the closed confirmation of Bcr-Abl kinase, dasatinib was designed to bind to both the open and closed form of the enzyme (Shah et al., 2004;Tokarski et al., 2006). Because of this binding property and the ability to inhibit multiple kinases, including Src, dasatinib is effective in tumors that are resistant to imatinib mesylate (O'Hare et al., 2005;Schittenhelm et al., 2006). Clinical studies have shown that dasatinib shows clinical response in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate treatment Hochhaus et al., 2006;Talpaz et al., 2006;Quintas-Cardama et al., 2007).Numerous in vitro and in vivo studies have been conducted with dasatinib in nonclinical species to understand its absorption, distribution, metabolism, and excretion (ADME) properties and gauge the suitability of these species as toxicological models Kamath et al., 2008). The metabolic profiles from in vitro studies in liver microsomes, and hepatocytes showed good correlation with the in vivo profiles generated after a single p.o. dose of [14 C]dasatinib to rats and monkeys. The primary metabolites of dasatinib Article, publication date, and citation information can be found at
Microsomal triglyceride transfer protein (MTP) is a lipid transfer protein that is required for the assembly and secretion of very low density lipoproteins by the liver and chylomicrons by the intestine. To further elucidate the nature of the lipid molecule binding and transport site on MTP, we have studied the relative rates at which MTP transports different lipid species. Assay conditions were chosen in which there were minimal changes in the physical properties of the substrate membranes so that transfer rates would reflect MTP-lipid interactions at a membrane surface. Lipid transport rates decreased in order of triglyceride > cholesteryl ester > diglyceride > cholesterol > phosphatidylcholine. Changes in the hydrophobic nature of a lipid molecule by the addition of a fatty acid, modulated the ability of MTP to transport it. Addition of one acyl chain from diglyceride to triglyceride, lysophosphatidylcholine to phosphatidylcholine, or cholesterol to cholesteryl ester increased the rate of MTP-mediated transport 10-fold. In contrast, the lipid transport rate was insensitive to the changes in the structure or charge of the polar head group on phospholipid substrates. Zwitterionic, net negative, or net positive charged phospholipid molecules were all transported at a comparable rate. The ability of MTP to transport lipids is strongly correlated to the binding of these lipids to MTP. Thus, MTP has a specific preference for binding and transporting nonpolar lipid compared with phospholipids, and within a class of lipid molecules, a decrease in polarity increases its tendency to be transported.
ABSTRACT:This study describes the in vitro metabolism of [ 14 C]dasatinib in liver tissue incubations from rat, monkey, and human and the in vivo metabolism in rat and monkey. Across species, dasatinib underwent in vitro oxidative metabolism to form five primary oxidative metabolites. In addition to the primary metabolites, secondary metabolites formed from combinations of the oxidative pathways and conjugated metabolites of dasatinib and its oxidative metabolites were also observed in hepatocytes incubations. In in vivo studies in rats and monkeys, the majority of the radioactive dose was excreted in the bile and feces. In bile duct-cannulated monkeys after an i.v. dose, 13.7% of the radioactive dose was excreted in the feces through direct secretion. Dasatinib comprised 56 and 26% of the area under the curve (AUC) (0-8 h) of total radioactivity (TRA) in plasma, whereas multiple metabolites accounted for the remaining 44 and 74% of the AUC (0-8 h) of TRA for rats and monkeys, respectively. In rat and monkey bile, dasatinib accounted for <12% of the excreted dose, suggesting that dasatinib was extensively metabolized before elimination. The metabolic profiles in bile were similar to the hepatocyte profiles. In both species, a large portion of the radioactivity excreted in bile (>29% of the dose) was attributed to N-oxides and conjugated metabolites. In rat and monkey feces, only the oxidative metabolites and their further oxidation products were identified. The absence of conjugative or N-oxide metabolites in the feces suggests hydrolysis or reduction, respectively, in the gastrointestinal tract before elimination.
gland, mammary tissue, lungs, kidneys, liver, and placenta. Compared with maternal tissues, a relatively low level of radioactivity was detected in fetal tissues. The concentrations of dasatinibequivalents in fetal liver and kidneys were <13% of the respective maternal organs. The C max of dasatinib-equivalents in fetal blood was approximately 39% of that in maternal blood; however, the AUC values were comparable. Fetal brain/blood ratios of C max and AUC 0-inf were approximately 1.58 and 1.48, respectively, which were much greater than the maternal ratios of 0.12 and 0.13. In summary, dasatinib was extensively distributed in maternal tissues and secreted into milk, but its penetration into the adult brain was limited. Transporters may be involved in mediating dasatinib distribution in the adult rat, whereas in the fetus, tissue and blood exposures were similar, suggesting that distribution in the fetus is predominantly mediated by diffusion.Dasatinib (SPRYCEL, BMS-354825) ( Fig. 1) is a potent, broadspectrum ATP-competitive inhibitor of five critical oncogenic tyrosine kinase families, including BCR-ABL, SRC, c-KIT, plateletderived growth factor  receptor, and ephrin receptor kinases (Lombardo et al., 2004;Schittenhelm et al., 2006;Tokarski et al., 2006). These kinases are involved in multiple forms of human malignancies (Daley et al., 1990;Lugo et al., 1990). Dasatinib is approximately 500-fold more potent than imatinib in inhibiting BCR-ABL. It binds to both the active and the inactive conformations of BCR-ABL, whereas imatinib only binds to the inactive state Talpaz et al., 2006;Tokarski et al., 2006;Quintas-Cardama et al., 2007). In clinical trials, dasatinib induced rapid and long-lasting major hematologic and cytogenetic responses in patients with imatinibresistant or intolerant blast crisis chronic myeloid leukemia (Guilhot et al., 2007;Hochhaus et al., 2007). Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios. Dasatinib is currently marketed for the treatment of adults with chronic, accelerated, or blast-phase chronic myeloid leukemia with resistance or intolerance to previous therapy including imatinib mesylate, and for the treatment of adults with Philadelphia chromosome positive (Ph ϩ ) acute lymphoblastic leukemia and lymphoid blast chronic myeloid leukemia with resistance or intolerance to previous therapy. Dasatinib is also under clinical development for the treatment of solid tumors.Dasatinib showed high intrinsic permeability in the Caco-2 cell model; however, the efflux ratio in this system was approximately 2-fold, suggesting that the compound may be a substrate for an intestinal efflux transporter (Kamath et al., 2008). Dasatinib showed a high volume of distribution (Ͼ3 l/kg) in each of the animal species (Kamath et al., 2008) and was highly metabolized in rats, monkeys, and humans (Christopher et al., 2008a,b). After intravenous administration of [14 C]dasatinib to bile duct-cannulated monkeys, approximately 10 and 67% of the dose was recovered in urine and b...
As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).
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