Drug Disposition and Response

2009 ◽  
pp. 27-43
Author(s):  
Robert B. Raffa
Keyword(s):  
Drug Disposition

Modulation of Expression and Activity of ABC Transporters by the Phytoestrogen Genistein. Impact on Drug Disposition

2016 ◽  
Vol 23 (13) ◽  
pp. 1370-1389 ◽  
Author(s):  
Juan Pablo Rigalli ◽  
Nadia Ciriaci ◽  
Aldo Domingo Mottino ◽  
Viviana Alicia Catania ◽  
María Laura Ruiz
Keyword(s):  
Abc Transporters ◽  
Drug Disposition ◽  
Expression And Activity

scholarly journals A Physiologically-Based Pharmacokinetic Framework for Prediction of Drug Exposure in Malnourished Children

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 204
Author(s):  
Erik Sjögren ◽  
Joel Tarning ◽  
Karen I. Barnes ◽  
E. Niclas Jonsson
Keyword(s):  
Body Composition ◽  
Drug Exposure ◽  
Drug Disposition ◽  
Pediatric Population ◽  
Model Performance ◽  
Vulnerable Population ◽  
Pbpk Modeling ◽  
Malnourished Children ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically-based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on (a) the differences in body composition between healthy and malnourished adults and (b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.

Drug Disposition in Humans: The Basis of Clinical Pharmacology.William A. Creasey

1980 ◽  
Vol 55 (1) ◽  
pp. 107-107
Author(s):  
Marcus M. Reidenberg
Keyword(s):  
Drug Disposition

scholarly journals Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

2021 ◽  
Author(s):  
Lawrence Howell ◽  
Rosalind E. Jenkins ◽  
Stephen Lynch ◽  
Carrie Duckworth ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Rna Polymerase Ii ◽  
Liver Tissue ◽  
Drug Disposition ◽  
Multiple Drug ◽  
Proteomic Profiling ◽  
Cytochrome P450 3A ◽  
Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

scholarly journals Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates

Pharmacology ◽  
2021 ◽  
pp. 1-6
Author(s):  
Pavla Pokorná ◽  
Martin Šíma ◽  
Birgit Koch ◽  
Dick Tibboel ◽  
Ondřej Slanař
Keyword(s):  
Linear Regression ◽  
Dosage Regimen ◽  
Regression Models ◽  
Drug Disposition ◽  
Prospective Trial ◽  
Full Term ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Linear Regression Models ◽  
Term Neonates

<b><i>Introduction:</i></b> Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. <b><i>Methods:</i></b> Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. <b><i>Results:</i></b> The median (IQR) central volume of distribution (Vd<sub>c</sub>) and clearance (CL) for sufentanil were 4.7 (4.1–5.4) L/kg and 0.651 (0.433–0.751) L/h/kg, respectively. Linear regression models showed relationship between Vd<sub>c</sub> (L) and GA (<i>r</i><sup>2</sup> = 0.3436; <i>p</i> = 0.0452) as well as BW (<i>r</i><sup>2</sup> = 0.4019; <i>p</i> = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78–2.48) μg/kg and 0.29 (95% CI: 0.22–0.37) μg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. <b><i>Discussion/Conclusion:</i></b> Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

scholarly journals Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 808
Author(s):  
Dirk Theile ◽  
Lelia Wagner ◽  
Cindy Bay ◽  
Walter Emil Haefeli ◽  
Johanna Weiss
Keyword(s):  
Mrna Expression ◽  
Interferon Alpha ◽  
Nuclear Factor Kappa B ◽  
Drug Disposition ◽  
Pregnane X Receptor ◽  
Nuclear Factor ◽  
Cyp3a4 Activity ◽  
Time Resolved ◽  
Nuclear Factor Kappa ◽  
Disposition Genes

Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-ĸB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-ĸB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross-talk between NF-ĸB activation and PXR suppression was evaluated by NF-ĸB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-ĸB activity 2-fold and suppressed PXR activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-ĸB. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate.

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