7 research outputs found

    Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies

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    PURPOSE: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2'-position of paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of DHA-paclitaxel. EXPERIMENTAL DESIGN: The blood distribution of DHA-paclitaxel was studied in vitro using equilibrium dialysis and in 23 cancer patients receiving the drug as a 2-h i.v. infusion (dose, 200-1100 mg/m(2)). RESULTS: In vitro, DHA-paclitaxel was found to bind extensively to human plasma (99.6 +/- 0.057%). The binding was concentration independent (P = 0.63), indicating a nonspecific, nonsaturable process. The fraction of unbound paclitaxel increased from 0.052 +/- 0.0018 to 0.055 +/- 0.0036 (relative increase, 6.25%; P = 0.011) with an increase in DHA-paclitaxel concentration (0-1000 microg/ml), suggesting weakly competitive drug displacement from protein-binding sites. The mean (+/- SD) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 +/- 0.029 microg.h/ml (at 660 mg/m(2)) to 0.624 +/- 0.216 microg.h/ml (at 1100 mg/m(2)), and was associated with the dose-limiting neutropenia in a maximum-effect model (R(2) = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m(2)) is similar to that achieved with paclitaxel on clinically relevant dose schedules. CONCLUSIONS: Extensive binding to plasma proteins may explain, in part, the unique pharmacokinetic profile of DHA-paclitaxel described previously with a small volume of distribution ( approximately 4 liters) and slow systemic clearance ( approximately 0.11 liters/h)

    MAT2A Mutations Predispose Individuals to Thoracic Aortic Aneurysms

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    Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIőĪ). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT IőĪ are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIőĪ enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIőĪ function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease
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