Quantitative Proteomics and Mechanistic Modeling of Transporter‐Mediated Disposition in Nonalcoholic Fatty Liver Disease

Vildhede, Anna; Kimoto, Emi; Pelis, Ryan M.; Rodrigues, A. David; Varma, Manthena V.

doi:10.1002/cpt.1699

Cited by 60 publications

(84 citation statements)

References 50 publications

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“…In NASH, steatosis is accompanied by inflammation, hepatocyte ballooning, and fibrosis. Importantly from a pharmacokinetic (PK) and drug safety viewpoint, there is growing evidence that proteins involved in drug absorption, distribution, metabolism, and excretion (ADME) are altered in patients with NASH 7–12 . There is, however, limited information about the functional consequences of NASH‐related changes in ADME proteins due to the small number of compounds that have been studied in clinical trials.…”

mentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

Sjöstedt

Brouwer

2020

Clin Pharma and Therapeutics

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Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, is increasing in prevalence. NASH‐related alterations in hepatic protein expression (e.g., transporters) and in overall physiology may affect drug exposure by altering drug disposition and elimination. The aim of this study was to build a physiologically‐based pharmacokinetic (PBPK) model to predict drug exposure in NASH by incorporating NASH‐related changes in hepatic transporters. Morphine and morphine‐3‐glucuronide (M3G) were used as model compounds. A PBPK model of morphine with permeability‐limited hepatic disposition was extended to include M3G disposition and enterohepatic recycling (EHR). The model captured the area under the plasma concentration‐time curve (AUC) of morphine and M3G after intravenous morphine administration within 0.82‐fold and 1.94‐fold of observed values from 3 independent clinical studies for healthy adult subjects (6, 10, and 14 individuals). When NASH‐related changes in multidrug resistance‐associated protein 2 (MRP2) and MRP3 were incorporated into the model, the predicted M3G mean AUC in NASH was 1.34‐fold higher compared to healthy subjects, which is slightly lower than the observed value (1.63‐fold). Exploratory simulations on other physiological changes occurring in NASH (e.g., moderate decreases in glomerular filtration rate and portal vein blood flow) revealed that the effect of transporter changes was most prominent. Additionally, NASH‐related transporter changes resulted in decreased morphine EHR, which could be important for drugs with extensive EHR. This study is an important first step to predict drug disposition in complex diseases such as NASH using PBPK modeling.

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confidence: 99%

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

Sjöstedt

Brouwer

2020

Clin Pharma and Therapeutics

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“…However, more precise proteomic quantitative information (mass spectrometry based methods) is also available. Those reports indicate no correlation between expression and protein abundance in the case of many transporters [13,[42][43][44][45][46][47]. Therefore, findings based only on transcriptome analysis may not reflect the real status of transporter abundance.…”

Section: Effects Of Liver Failure On Hepatic Drug Transportersmentioning

confidence: 98%

Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract

Droździk

Oswald

Droździk

2020

IJMS

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Emerging information suggests that liver pathological states may affect the expression and function of membrane transporters in the gastrointestinal tract and the kidney. Altered status of the transporters could affect drug as well as endogenous compounds handling with subsequent clinical consequences. It seems that changes in intestinal and kidney transporter functions provide the compensatory activity of eliminating endogenous compounds (e.g., bile acids) generated and accumulated due to liver dysfunction. A literature search was conducted on the Ovid and PubMed databases to select relevant in vitro, animal and human studies that have reported expression, protein abundance and function of the gastrointestinal and kidney operating ABC (ATP-binding cassette) transporters and SLC (solute carriers) carriers. The accumulated data suggest that liver failure-associated transporter alterations in the gastrointestinal tract and kidney may affect drug pharmacokinetics. The altered status of drug transporters in those organs in liver dysfunction conditions may provide compensatory activity in handling endogenous compounds, affecting local drug actions as well as drug pharmacokinetics.

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“…For example, in one approach, targeted proteomics has succeeded in identifying changes (in most cases reduction) in concentrations of hepatic drug transporters in people with NAFLD compared to healthy ones. The reduction in hepatic drug transporters can have a major impact on pharmacokinetics and can drive clinical development decisions as well as dosing recommendations [ 155 ].…”

Section: Proteomicsmentioning

confidence: 99%

The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease

2020

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Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.

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Quantitative Proteomics and Mechanistic Modeling of Transporter‐Mediated Disposition in Nonalcoholic Fatty Liver Disease

Cited by 60 publications

References 50 publications

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract

The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease

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