MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study

Holmstock, Nico; Oorts, Marlies; Snoeys, Jan; Annaert, Pieter

doi:10.1124/dmd.117.079467

Cited by 14 publications

(9 citation statements)

References 41 publications

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“…LPV has been reported to induce its own metabolism (ie, CYP3A) but also other CYP (eg, CYP2B6) through PXR activation 42 and constitutes a potent inhibitor of ABCC2. 43,44 Meanwhile, the boosters, RTV and COB, exert slightly different effects: both are capable of inhibiting CYP3A, OATP1B1, and OATP1B3, while RTV may also induce other CYP isoforms. [45][46][47] RTV also increases the biotransformation of some drugs metabolized by glucuronidation catalyzed by UGT, although the clinical relevance of this effect is not clear.…”

Section: Mode Of Action and Pharmacokineticsmentioning

confidence: 99%

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Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

Elens

Langman

Hesselink

et al. 2020

Therapeutic Drug Monitoring

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Background: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. Methods: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. Results: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. Conclusions: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.

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Section: Mode Of Action and Pharmacokineticsmentioning

confidence: 99%

“…As mentioned above, LPV is a potent inhibitor of ABCC2 43 and the boosters have the potential to reduce the hepatic uptake mediated through OATP inhibition. The net effect would thus be a decrease of MPAG biliary excretion and consequently, decreasing entero-hepatic-recirculation, lowering MPA exposure.…”

Section: Mycophenolate Mofetilmentioning

confidence: 99%

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

Elens

Langman

Hesselink

et al. 2020

Therapeutic Drug Monitoring

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“…If we compare these Mrp3 data with the better known and investigated rat and human MRP2 transporter isoforms, we can conclude that there is overlap in inhibitory potential since e.g. benzbromarone and tipranavir are also known inhibitors of Mrp2/MRP2 (Gilibili et al, 2017;Holmstock et al, 2018). These confirmed hits can be used as diagnostic inhibitors later on to investigate Mrp3 mediated efflux of potential compounds.…”

Section: Discussionmentioning

confidence: 91%

Identification of novel inhibitors of rat Mrp3

Vocht

Buyck

Deferm

et al. 2021

European Journal of Pharmaceutical Sciences

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“…In addition, a series of studies have reported LPV as an important inhibitor of multidrug resistance–associated protein 2 (MRP2), an apical efflux transporter in hepatocytes, contributing to the excretion of bile acids ( 86 , 87 ). In a more recent study evaluating the biliary excretion index (BEI) of 5( 6 )-carboxy-29, 79 dichlorofluorescein (CDF) through confocal imaging, the inhibitory effects of LPV was further supported ( 88 ). In another recent study, hepatotoxicity of PIs, LPV and, RTV, was reported to interfere with ER-Golgi trafficking via inhibition of Ras converting CAAX endopeptidase-1 (RCE1) and its potential substrates, leading to cellular stress responses and fatty liver disease ( 89 ).…”

Section: Discussionmentioning

confidence: 99%

Drug-Induced Liver Injury in COVID-19 Patients: A Systematic Review

et al. 2021

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Introduction: The severity of COVID-19 may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity has been associated with using some medications in the management of COVID-19 patients. However, limited studies had systematically investigated the evidence of drug-induced liver injury (DILI) in COVID-19 patients. Thus, this study aimed to examine DILI in COVID-19 patients.Methods: A systematic search was carried out in PubMed/Medline, EMBASE, and Web of Science up to December 30, 2020. Search items included “SARS-CoV-2”, “Coronavirus,” COVID-19, and liver injury.Results: We included 22 related articles. Among included studies, there was five case report, five case series, four randomizes control trial (RCT), seven cohort studies, and one cross-sectional study. The drugs included in this systematic review were remdesivir, favipiravir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir. Among included studies, some studies revealed a direct role of drugs, while others couldn't certainly confirm that the liver injury was due to SARS-CoV-2 itself or administration of medications. However, a significant number of studies reported that liver injury could be attributable to drug administration.Discussion: Liver injury in COVID-19 patients could be caused by the virus itself or the administration of some types of drug. Intensive liver function monitoring should be considered for patients, especially patients who are treated with drugs such as remdesivir, lopinavir/ritonavir, and tocilizumab.

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MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study

Cited by 14 publications

References 41 publications

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

Identification of novel inhibitors of rat Mrp3

Drug-Induced Liver Injury in COVID-19 Patients: A Systematic Review

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