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Article ; Online: Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity.

Saran, Chitra / Brouwer, Kim L R

2023 Volume 51, Issue 7-8, Page(s) 405–413

Abstract: Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure. One mechanism of DILI is altered bile acid homeostasis and involves several hepatic ... ...

Abstract	Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure. One mechanism of DILI is altered bile acid homeostasis and involves several hepatic bile acid transporters. Functional impairment of some hepatic bile acid transporters by drugs, disease, or genetic mutations may lead to toxic accumulation of bile acids within hepatocytes and increase DILI susceptibility. This review focuses on the role of hepatic bile acid transporters in DILI. Model systems, primarily
MeSH term(s)	Animals ; Humans ; Chemical and Drug Induced Liver Injury/etiology ; Drug-Related Side Effects and Adverse Reactions ; Bile Acids and Salts ; Carrier Proteins ; Membrane Glycoproteins
Chemical Substances	bile acid binding proteins ; Bile Acids and Salts ; Carrier Proteins ; Membrane Glycoproteins
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/01926233231212255
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Article ; Online: Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD).

Adiwidjaja, Jeffry / Spires, Jessica / Brouwer, Kim L R

Pharmaceutical research

2024 Volume 41, Issue 3, Page(s) 441–462

Abstract: Purpose: This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of ... ...

Abstract	Purpose: This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. Methods: A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, Results: PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of Conclusion: A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.
MeSH term(s)	Humans ; Non-alcoholic Fatty Liver Disease/drug therapy ; Midazolam/pharmacokinetics ; Cytochrome P-450 Enzyme System/metabolism ; Models, Biological ; Metformin ; Morphine Derivatives
Chemical Substances	Midazolam (R60L0SM5BC) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Metformin (9100L32L2N) ; Morphine Derivatives
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-024-03664-8
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Article: Effect of mTOR inhibitors on sodium taurocholate cotransporting polypeptide (NTCP) function

Saran, Chitra / Ho, Henry / Honkakoski, Paavo / Brouwer, Kim L R

Frontiers in pharmacology

2023 Volume 14, Page(s) 1147495

Abstract: The sodium taurocholate cotransporting polypeptide (NTCP; gene ... ...

Abstract	The sodium taurocholate cotransporting polypeptide (NTCP; gene name
Language	English
Publishing date	2023-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1147495
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Article ; Online: Application of Pharmacokinetic Modeling to Characterize Hepatobiliary Disposition of Imaging Agents and Alterations due to Liver Injury in Isolated Perfused Rat Livers.

Jeong, Angela / Pastor, Catherine M / Brouwer, Kim L R

Pharmaceutical research

2023 Volume 40, Issue 11, Page(s) 2513–2523

Abstract: Background: Understanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [: Methods: A multi-compartmental pharmacokinetic (PK) model describing MEB and BOPTA disposition in isolated perfused ...

Abstract	Background: Understanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [ Methods: A multi-compartmental pharmacokinetic (PK) model describing MEB and BOPTA disposition in isolated perfused rat livers (IPRLs) was developed. The PK model was simultaneously fit to MEB and BOPTA concentration-time data in the extracellular space, hepatocytes, bile canaliculi, and sinusoidal efflux in livers from healthy rats, and to BOPTA concentration-time data in rats pretreated with monocrotaline (MCT). Results: The model adequately described MEB and BOPTA disposition in each compartment. The hepatocyte uptake clearance was much higher for MEB (55.3 mL/min) than BOPTA (6.67 mL/min), whereas the sinusoidal efflux clearance for MEB (0.000831 mL/min) was lower than BOPTA (0.0127 mL/min). The clearance from hepatocytes to bile (CL Conclusion: A PK model developed to characterize MEB and BOPTA disposition in IPRLs was used to quantify changes in the hepatobiliary disposition of BOPTA caused by MCT pretreatment of rats to induce liver toxicity. This PK model could be applied to simulate changes in the hepatobiliary disposition of these imaging agents in rats in response to altered hepatocyte uptake or efflux associated with disease, toxicity, or drug-drug interactions.
MeSH term(s)	Rats ; Animals ; Liver/diagnostic imaging ; Liver/metabolism ; Hepatocytes ; Organometallic Compounds/pharmacokinetics ; Bile ; Biological Transport
Chemical Substances	Organometallic Compounds
Language	English
Publishing date	2023-06-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-023-03549-2
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Article ; Online: Lipidomics profiles in hepatocytes from nonalcoholic steatohepatitis patients differ markedly from in vitro-induced steatotic hepatocytes.

Kralj, Thomas / Khatri, Raju / Brouwer, Kenneth R / Brouwer, Kim L R / Creek, Darren J

FEBS letters

2022 Volume 596, Issue 11, Page(s) 1445–1452

Abstract: Nonalcoholic steatohepatitis (NASH) is a severe form of liver injury that can be caused by a variety of stimuli and has a significant mortality rate. A common technique to induce in vitro steatosis involves culturing primary human hepatocytes (PHH) in ... ...

Abstract	Nonalcoholic steatohepatitis (NASH) is a severe form of liver injury that can be caused by a variety of stimuli and has a significant mortality rate. A common technique to induce in vitro steatosis involves culturing primary human hepatocytes (PHH) in fatty acid-enriched media. This study compared the lipidome of PHH cultured in fatty acid-enriched media to hepatocytes from patients with NASH and healthy controls. Hepatocytes from NASH patients displayed increased total cellular abundance of glycerolipids and phospholipids compared to healthy control hepatocytes. PHH cultured in fatty acid-enriched media demonstrated increased glycerolipids. However, these culture conditions did not induce elevated phospholipid levels. Thus, culturing PHH in fatty acid-enriched media has limited capacity to emulate the environment of hepatocytes in NASH patients.
MeSH term(s)	Fatty Acids ; Hepatocytes ; Humans ; Lipidomics ; Liver ; Non-alcoholic Fatty Liver Disease ; Phospholipids
Chemical Substances	Fatty Acids ; Phospholipids
Language	English
Publishing date	2022-02-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14318
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Article ; Online: Analytical and Omics-Based Advances in the Study of Drug-Induced Liver Injury.

Kralj, Thomas / Brouwer, Kim L R / Creek, Darren J

Toxicological sciences : an official journal of the Society of Toxicology

2021 Volume 183, Issue 1, Page(s) 1–13

Abstract: Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1-1.5 million patients annually, and remains a major challenge during drug development-toxicity and safety concerns are the second-highest reason for drug candidate failure. The ... ...

Abstract	Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1-1.5 million patients annually, and remains a major challenge during drug development-toxicity and safety concerns are the second-highest reason for drug candidate failure. The future prevalence of DILI can be minimized by developing a greater understanding of the biological mechanisms behind DILI. Both qualitative and quantitative analytical techniques are vital to characterizing and investigating DILI. In vitro assays are capable of characterizing specific aspects of a drug's hepatotoxic nature and multiplexed assays are capable of characterizing and scoring a drug's association with DILI. However, an even deeper insight into the perturbations to biological pathways involved in the mechanisms of DILI can be gained through the use of omics-based analytical techniques: genomics, transcriptomics, proteomics, and metabolomics. These omics analytical techniques can offer qualitative and quantitative insight into genetic susceptibilities to DILI, the impact of drug treatment on gene expression, and the effect on protein and metabolite abundance. This review will discuss the analytical techniques that can be applied to characterize and investigate the biological mechanisms of DILI and potential predictive biomarkers.
MeSH term(s)	Biomarkers ; Chemical and Drug Induced Liver Injury/genetics ; Genomics ; Humans ; Liver ; Metabolomics ; Proteomics
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfab069
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Article ; Online: New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments.

Pastor, Catherine M / Brouwer, Kim L R

Drug metabolism and disposition: the biological fate of chemicals

2021 Volume 50, Issue 1, Page(s) 58–64

Abstract: Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study ... ...

Abstract	Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver.
MeSH term(s)	Aniline Compounds/pharmacokinetics ; Animals ; Bile Canaliculi/metabolism ; Biliary Tract/diagnostic imaging ; Contrast Media/pharmacokinetics ; Diagnostic Imaging ; Extracellular Space/metabolism ; Genes, erbB-2/genetics ; Glycine/pharmacokinetics ; Hepatocytes/metabolism ; In Vitro Techniques ; Liver/diagnostic imaging ; Liver/metabolism ; Male ; Models, Biological ; Nonlinear Dynamics ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Aniline Compounds ; Contrast Media ; mebrofenin (7PV0B6ED98) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.121.000546
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Article: Lipidomics profiles in hepatocytes from nonalcoholic steatohepatitis patients differ markedly from in vitro‐induced steatotic hepatocytes

Kralj, Thomas / Khatri, Raju / Brouwer, Kenneth R. / Brouwer, Kim L. R. / Creek, Darren J.

FEBS letters. 2022 June, v. 596, no. 11

2022

Abstract	Nonalcoholic steatohepatitis (NASH) is a severe form of liver injury that can be caused by a variety of stimuli and has a significant mortality rate. A common technique to induce in vitro steatosis involves culturing primary human hepatocytes (PHH) in fatty acid‐enriched media. This study compared the lipidome of PHH cultured in fatty acid‐enriched media to hepatocytes from patients with NASH and healthy controls. Hepatocytes from NASH patients displayed increased total cellular abundance of glycerolipids and phospholipids compared to healthy control hepatocytes. PHH cultured in fatty acid‐enriched media demonstrated increased glycerolipids. However, these culture conditions did not induce elevated phospholipid levels. Thus, culturing PHH in fatty acid‐enriched media has limited capacity to emulate the environment of hepatocytes in NASH patients.
Keywords	fatty liver ; hepatocytes ; humans ; lipidomics ; liver ; mortality ; phospholipids
Language	English
Dates of publication	2022-06
Size	p. 1445-1452.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14318
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Article ; Online: Mechanistic Modeling of the Hepatic Disposition of Estradiol-17

Ito, Katsuaki / Sjöstedt, Noora / Brouwer, Kim L R

Drug metabolism and disposition: the biological fate of chemicals

2019 Volume 48, Issue 2, Page(s) 116–122

Abstract: Estradiol- ... ...

Abstract	Estradiol-17
Language	English
Publishing date	2019-11-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.119.088898
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Article ; Online: Developing evidence-based resources for evaluating postgraduate trainees in the biomedical sciences.

McLaughlin, Jacqueline E / Layton, Rebekah L / Watkins, Paul B / Nicholas, Robert A / Brouwer, Kim L R

PloS one

2022 Volume 17, Issue 12, Page(s) e0278297

Abstract: Postgraduate trainees elevate the academic strength of institutions by conducting research, promoting innovation, securing grant funding, training undergraduate students, and building alliances. Rigorous and systematic program evaluation can help ensure ... ...

Abstract	Postgraduate trainees elevate the academic strength of institutions by conducting research, promoting innovation, securing grant funding, training undergraduate students, and building alliances. Rigorous and systematic program evaluation can help ensure that postgraduate training programs are achieving the program's intended outcomes. The purpose of this project was to develop evidence-based evaluation tools that could be shared across federally funded biomedical training programs to enhance program evaluation capacity. This manuscript describes the evidence-based process used to determine program evaluation needs of these programs at a research-intensive university. Using a multi-phased sequential exploratory mixed methods approach, data were collected from trainees, employers, leaders, and program directors. Data analyses included document analysis of program plans, inductive coding of focus groups and interviews, and descriptive analysis of surveys. Two overarching categories-Trainee Skills and Program Characteristics-were identified including six themes each. Program directors prioritized communication, social and behavioral skills, and collaboration as the trainee skills that they needed the most help evaluating. Furthermore, program directors prioritized the following program characteristics as those that they needed the most help evaluating: training environment, trainee outcomes, and opportunities offered. Surveys, interview scripts, and related resources for the categories and themes were developed and curated on a publicly available website for program directors to use in their program evaluations.
MeSH term(s)	Humans ; Research Personnel ; Education, Graduate ; Universities ; Program Evaluation ; Program Development ; Biomedical Research/education
Language	English
Publishing date	2022-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0278297
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