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Davis, CA, United States

Ross A.B.,Nestle | Vuong L.T.,Vitalea Science | Ruckle J.,Covance | Synal H.A.,ETH Zurich | And 14 more authors.
American Journal of Clinical Nutrition | Year: 2011

Background: To our knowledge, there is no direct information on lycopene metabolism in humans. Objective: The objective of this study was to quantify the long-term human bioavailability of lycopene in plasma and skin after a single dose of 14C-lycopene and to profile the metabolites formed. Design: We preselected 2 male subjects as lycopene absorbers and gave them an oral dose of 10 mg synthetic lycopene combined with ≈6 μg [6,6′,7,7′- 14C]lycopene (≈30,000 Bq; 92% trans lycopene). The appearance of 14C in plasma, plasma triacylglycerol-rich lipoprotein (TRL) fraction, urine, expired breath carbon dioxide, and skin biopsies was measured over 42 d. The 14C in lycopene-isomer fractions from plasma and TRL fraction was measured to assess the isomerization of lycopene in vivo. Results: We quantified 14C from 14C-lycopene in plasma, the plasma TRL fraction, expired carbon dioxide, urine, and skin. The time to maximum concentration (tmax) of total 14C-lycopene in plasma was 6 h, and the elimination half-life (t1/2) was 5 d, which were different from the tmax and t1/2 of unlabeled lycopene (0.5 and 48 d, respectively). 14C-Lycopene was extensively isomerized after dosing as a 92% all-trans isomer at dosing but changed to 50% trans, 38% 5 cis, 1%9cis, and 11% other cis isomers after 24 h. A similar pattern of isomerization was seen in plasma TRL fractions. Conclusions: Lycopene was extensively isomerized after dosing and rapidly metabolized into polar metabolites excreted into urine with the rapid peak of 14CO 2 after dosing, which implies that β-oxidation was involved in the lycopene metabolism. Lycopene or its metabolites were detected in skin for up to 42 d. © 2011 American Society for Nutrition. Source


Aklamati E.K.,University of California at Davis | Mulenga M.,Tropical Diseases Research Center | Dueker S.R.,Vitalea Science | Buchholz B.A.,Lawrence Livermore National Laboratory | And 4 more authors.
Journal of Nutrition | Year: 2010

A survey indicated that high-dose vitamin A (HD-VA) supplements had no apparent effect on vitamin A (VA) status, assessed by serum retinol concentrations, of Zambian children < 5 y of age. To explore possible reasons for the lack of response, we quantified absorption, retention, and urinary elimination of either a single HD-VA supplement (209.8 μmol; 60 mg) or a smaller dose of stable isotope (SI)-labeled VA (17.5 μmol; 5 mg), which was used to estimate VA pool size, in 3- to 4-y-old Zambian boys (n = 4 for each VA dose). A tracer dose of [ 14C 2]-labeled VA (0.925 kBq; 25 nCi) was coadministered with the HD-VA supplement or SI-labeled VA, and 24-h stool and urine samples were collected for 3 and 7 consecutive days, respectively, and 24-h urine samples at 4 later time points. Accelerator MS was used to quantify 14C in stool and urine. Estimates of absorption, retention, and the urinary elimination rate (UER) were 83.8 ± 7.1%, 76.3 ± 6.7%, and 1.9 ± 0.6%/d, respectively, for the HD-VA supplement and 76.5 ± 9.5%, 71.1 ± 9.4%, and 1.8 ± 1.2%/d, respectively, for the SI-labeled VA. Mean estimates of absorption, retention, and the UER did not differ by size of the VA dose administered. Estimated absorption and retention were negatively associated with reported fever (r = -0.83; P =0.011). The HD-VA supplement and SI-labeled VA were adequately absorbed, retained, and utilized in apparently healthy Zambian preschool-age boys; absorption and retention may be affected by recent fever. © 2010 American Society for Nutrition. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 130.20K | Year: 2007

DESCRIPTION (provided by applicant): Azidothymidine (3'-azido-3'-deoxythymidine, AZT) is the most widely used drug to reduce mother-to child transmission of HIV in most countries. To be effective, AZT must undergo multiple phosphorylation steps in the lymphocytes to the prodrug triphosphate derivative. It is this derivative that is a substrate for viral reverse transcriptase, resulting in termination of the viral replication and thus mitigating the progression of viral growth. There are hazards associated with genotoxicity (later life cancer development) and mitochondrial function that place new methods for assessment of drug disposition in neonates and children a high priority. There is very little known about the drug disposition of nucleoside/nucleotide analogs in pediatrics populations; given the magnitude and frequency to which the youngest of children globally are exposure to these drugs, better clinical pharmacology tools are a high priority. We now have the tools to study drug disposition in pediatrics using Accelerator Mass Spectrometry (AMS). AMS achieves attomole (10-18) sensitivity for 14 C isotopic labels, the lowest levels of any known analytical instrument. Perinatal exposures and infant incorporation of 14 C-AZT may be quantified by AMS safely using permissible blood samples. For Phase 1 of this SBIR, we propose to develop and validate a method to quantify intracellular AZT triphosphate concentrations and final DNA incorporation within lymphocytes isolated from defensibly small blood volumes ( work will demonstrate capability for quantitation of pharmacodynamic parameters, intracellular concentrations and DNA incorporation, that may provide robust measures of target cell exposures from circulating doses. For Phase 2, we will apply this methodology in pediatric populations exposed to AZT to validate the platform and gain new insights into the pediatric response to AZT therapy. The ultimate aim of this work is to obtain a robust analytical platform to be applied as a service for clinical pharmacology to improve pediatric extrapolation from adult therapies. This work is significant as it could answer critical questions including appropriate oral dosing of genotoxic drugs such as nucleoside analogs, during pregnancy, labor and the immediate postpartum period, as well as investigating infant DNA incorporation of the active drug metabolites following in utero exposure. This proposal describes a new method made possible by a key technological innovation: ultra sensitive detection of 14 C-labeled compounds by Accelerator Mass Spectrometry. AMS enables the study of drug metabolism and toxicity in pediatric patients by allowing direct quantitation of intracellular uptake of a minute quantity of labeled drug metabolites from a very small blood sample. The isotopic label is radioactive, but the amount needed for AMS tracing is less than an infant's natural 14 C content. This work is significant as it could answer critical questions including appropriate oral dosing of genotoxic drugs such as nucleoside analogs, during pregnancy, labor and the immediate postpartum period, as well as investigating infant DNA incorporation of the active drug metabolites following in utero exposure. Phase I will demonstrate lack of matrix effects and the linearity of quantitation as well as quantify cellular drug content in archived blood samples. Phase 2 will demonstrate the relations between plasma and cellular concentrations in two large on-going clinical trials within the Pediatric AIDS Clinical Trials Group (PACTG) and HIV Perinatal Transition Network (HPTN).


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 165.95K | Year: 2006

DESCRIPTION (provided by applicant): Vitamin B12 (cobalamin) deficiency is a significant public health problem among the elderly. Deficiency can lead to a wide spectrum of hematological (pernicious anemia) and neurological disorders (dementia) which are usually reversible by early diagnosis and prompt treatment. The primary causes of deficiency is malabsorption due to a lack of intrinsic factor and gastric atrophy. Accurate diagnostic tests for vitamin B12 malabsorption are needed because the symptoms attributable to mild vitamin B12 deficiency, neurological dysfunction and dementia, are non-specific and difficult to diagnose. The currently used procedure for assessing B12 malabsorption is the Schilling Urinary Excretion Test, first introduced in 1953. While this radioisotopic test has made great advances in understanding vitamin B12 related disease, it is imprecise and cumbersome (requires 24 hr urine collections). As a result, the underlying causes of B12 deficiency are frequently not addressed, despite the chronic and degenerative aspects of the problem. The market for a simple replacement has been estimated at up to 1,000,000 tests per year in continental USA, although only an estimated 40,000 Schilling tests per year are currently administered. This proposal describes a new absorption test method based upon a single finger-prick measurement that can be applied to pediatric populations as well as adults. The working title for the new assay is VSI-B12. The test is made possible by two key technological innovations: an inexpensive biosynthetic system for production of isotopic (14C) vitamin B12 (dubbed tracer B12), and an ultra sensitive detection of the tracer B12 by Accelerator Mass Spectrometry, a tool that achieves zeptomole (10-21) sensitivity towards C isotopes, 14 the lowest levels of any known analytical instrument. Using this approach, the absorption of an oral dose of Tracer B12 can be quantified in a single drop of blood using harmlessly small radioactive doses (25 nanoCuries). For Phase 1, we propose a plan for optimization of the bacterial vitamin B12 labeling system so as to more efficiently produce tracer B12 for further clinical evaluation (Phase 2). Specific Aims of this proposal are: 1. Perform a set experiments to optimize biosynthesis of Tracer B12 from our engineered bacterial system. 2. Biosynthesize and purify 100 test doses to be administered orally in Phase 2. 3. Identify clinical PI's who have experience with the Schilling test and willingness to serve as collaborative partners in the development of VSI-B12 The work has significance as it should lead to a convenient diagnostic test for the clinical B12 malabsorption that can be employed in the clinic or in research settings. The format described, once successfully introduced to the research community, should stimulate similar development in other diagnostic areas, and could usher in a new era for tracer diagnostics where minute quantities of an appropriate 14 C probe are quantified by Accelerator Mass Spectrometry from microliter-sized specimens. This proposal describes a new test method made possible by two key technological innovations: an inexpensive biosynthetic system for production of isotopic (14C) vitamin B12 (Tracer B12), and an ultra sensitive detection of the Tracer B12 by Accelerator Mass Spectrometry. The work is significant as it would lead to a needed convenient diagnostic test for the clinical B12 malabsorption that can be employed in the clinic or in research settings.


Xu X.,Bristol Myers Squibb | Dueker S.R.,Vitalea Science | Christopher L.J.,Bristol Myers Squibb | Lohstroh P.N.,Vitalea Science | And 8 more authors.
Bioanalysis | Year: 2012

Background: An absolute bioavailability study that utilized an intravenous [14C]microdose was conducted for saxagliptin (Onglyza®), a marketed drug product for the treatment of Type 2 diabetes mellitus. Concentrations of [14C]saxagliptin were determined by accelerator MS (AMS) after protein precipitation, chromatographic separation by UPLC and analyte fraction collection. A series of investigative experiments were conducted to maximize the release of the drug from high-affinity receptors and nonspecific adsorption, and to determine a suitable quantitation range. Results: A technique-appropriate validation demonstrated the accuracy, precision, specificity, stability and recovery of the AMS methodology across the concentration range of 0.025 to 15.0 dpm/ml (disintegration per minute per milliliter), the equivalent of 1.91-1144 pg/ml. Based on the study sample analysis, the mean absolute bioavailability of saxagliptin was 50% in the eight subjects with a CV of 6.6%. Incurred sample reanalysis data fell well within acceptable limits. Conclusion: This study demonstrated that the optimized sample pretreatment and chromatographic separation procedures were critical for the successful implementation of an UPLC plus AMS method for [14C] saxagliptin. The use of multiple-point standards are useful, particularly during method development and validation, to evaluate and correct for concentration-dependent recovery, if observed, and to monitor and control process loss and operational variations. © 2012 Future Science Ltd. Source

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