| 1. |
- Bhatt, Deepak Kumar, et al.
(författare)
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Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver
- 2019
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 105:1, s. 131-141
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The American Society for Clinical Pharmacology and Therapeutics. The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.
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| 2. |
- Prasad, Bhagwat, et al.
(författare)
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Quantitative proteomics for translational pharmacology and precision medicine : state of the art and future outlook
- 2024
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Ingår i: Drug Metabolism And Disposition. - 0090-9556 .- 1521-009X. ; 52:7
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 20 years, quantitative proteomics has contributed a wealth of protein expression data, which are currently used for a variety of systems pharmacology applications, as a complement or a surrogate for activity of the corresponding proteins. A symposium at the 25th North American ISSX meeting, in Boston, in September 2023, was held to explore current and emerging applications of quantitative proteomics in translational pharmacology and strategies for improved integration into model-informed drug development based on practical experience of each of the presenters. A summary of the talks and discussions is presented in this perspective alongside future outlooks that were outlined for future meetings.
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| 3. |
- Prasad, Bhagwat, et al.
(författare)
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Toward a Consensus on Applying Quantitative Liquid Chromatography-Tandem Mass Spectrometry Proteomics in Translational Pharmacology Research : A White Paper
- 2019
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 106:3, s. 525-543
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative translation of information on drug absorption, disposition, receptor engagement, and drug-drug interactions from bench to bedside requires models informed by physiological parameters that link in vitro studies to in vivo outcomes. To predict in vivo outcomes, biochemical data from experimental systems are routinely scaled using protein quantity in these systems and relevant tissues. Although several laboratories have generated useful quantitative proteomic data using state-of-the-art mass spectrometry, no harmonized guidelines exit for sample analysis and data integration to in vivo translation practices. To address this gap, a workshop was held on September 27 and 28, 2018, in Cambridge, MA, with 100 experts attending from academia, the pharmaceutical industry, and regulators. Various aspects of quantitative proteomics and its applications in translational pharmacology were debated. A summary of discussions and best practices identified by this expert panel are presented in this "White Paper" alongside unresolved issues that were outlined for future debates.
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| 4. |
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- 2017
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Ingår i: Physical Review D. - 2470-0010 .- 2470-0029. ; 96:2
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Tidskriftsartikel (refereegranskat)
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