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Militello in Val di Catania, Italy

Ng E.S.M.,Pharmacokinetic Unit | Kangarloo S.B.,Pharmacokinetic Unit | Daly A.,Tom Baker Cancer Center
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2013

An improved quantitative assay was developed and validated for fludarabine in human plasma. Fludarabine and its internal standard, cladribine, were separated on a C18 analytical column after sample purification by strong anion-exchange solid-phase extraction. Quantitation was performed by electrospray triple-quadrupole mass spectrometry in positive ionization mode using multiple-reaction monitoring. This assay had excellent inter- and intra-assay precisions within 8%, and accuracies ranging from 100 to 116%. The method was linear within the concentration range of 0.2-250ng/mL using 100μL of plasma with mean R2=0.9999. The extraction recoveries were 85% for fludarabine and 95% for the internal standard, which represent a significant improvement over the previously published methods. We utilized this method for pharmacokinetic (PK) investigations in 215 patients. Interference peaks constantly observed in each blank plasma sample were well resolved from fludarabine using our optimized LC-MS/MS conditions, demonstrating the reliability of this improved assay. The validated method will be further applied to PK studies within our bone marrow transplant program, which will allow for optimal dose and scheduling of fludarabine in these patients. © 2013 Elsevier B.V. Source


Ng E.S.M.,Pharmacokinetic Unit | Kangarloo S.B.,Pharmacokinetic Unit | Konno M.,Pharmacokinetic Unit | Paterson A.,University of Calgary | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: Tamoxifen is a key therapeutic option for breast cancer treatment. Understanding its complex metabolism and pharmacokinetics is important for dose optimization. We examined the possibility of utilizing archival formalin-fixed paraffin-embedded (FFPE) tissue as an alternative sample source for quantification since well-annotated retrospective samples were always limited. Methods: Six 15 μm sections of FFPE tissues were deparaffinized with xylene and purified using solid-phase extraction. Tamoxifen and its metabolites were separated and detected by liquid chromatography-tandem mass spectrometry using multiple-reaction monitoring. Results: This method was linear between 0.4 and 200 ng/g for 4-hydroxy-tamoxifen and endoxifen, and 4-2,000 ng/g for tamoxifen and N-desmethyl-tamoxifen. Inter- and intra-assay precisions were <9 %, and mean accuracies ranged from 81 to 106 %. Extraction recoveries were between 83 and 88 %. The validated method was applied to FFPE tissues from two groups of patients, who received 20 mg/day of tamoxifen for >6 months, and were classified into breast tumor recurrence and non-recurrence. Our preliminary data show that levels of tamoxifen metabolites were significantly lower in patients with recurrent cancer, suggesting that inter-individual variability in tamoxifen metabolism might partly account for the development of cancer recurrence. Nevertheless, other causes such as non-compliance or stopping therapy of tamoxifen could possibly lead to the concentration differences. Conclusions: The ability to successfully study tamoxifen metabolism in such tissue samples will rapidly increase our knowledge of how tamoxifen's action, metabolism and tissue distribution contribute to breast cancer control. However, larger population studies are required to understand the underlying mechanism of tamoxifen metabolism for optimization of its treatment. © 2014 The Author(s). Source


Vitale D.C.,Pharmacokinetic Unit
European journal of drug metabolism and pharmacokinetics | Year: 2013

Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones. Source


Russell J.A.,Foothills Hospital and Tom Baker Cancer Center | Kangarloo S.B.,Pharmacokinetic Unit | Williamson T.,Queens University | Chaudhry M.A.,Foothills Hospital and Tom Baker Cancer Center | And 14 more authors.
Biology of Blood and Marrow Transplantation | Year: 2013

A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Buexposures exceeding 6000μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt toidentify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50mg/m2 on days -6 to -2 and i.v. Bu 3.2mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P=.014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814μM/min and >4993μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P=.004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P=.021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P=.018). Bu exposures between 4440 and 4993μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD. © 2013 American Society for Blood and Marrow Transplantation. Source


Vitale D.C.,Pharmacokinetic Unit | Piazza C.,Pharmacokinetic Unit | Melilli B.,Pharmacokinetic Unit | Drago F.,Pharmacokinetic Unit | And 2 more authors.
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2012

Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones. © 2012 Springer-Verlag France. Source

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