Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment

El‐Khateeb, Eman; Achour, Brahim; Al‐Majdoub, Zubida M.; Barber, Jill; Rostami‐Hodjegan, Amin

doi:10.1021/acs.molpharmaceut.1c00462

Cited by 44 publications

(68 citation statements)

References 60 publications

(103 reference statements)

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“…Mostly similar results were reported by Billington et al [7] in chronic hepatitis C infection (but not stratified according to the liver functional state). An analysis of a small number of hepatitis C livers was also reported by El-Khateeb et al [9], who revealed downregulation of MRP2 and OATP2B1 proteins. A summary of the available proteomic information about drug transporters and carriers in hepatitis C is presented in Table 2.…”

Section: Discussionsupporting

confidence: 66%

“…Analysis of transporter abundance of all studies with hepatitis C patients suggests downregulation of NTCP, BSEP, and OCT1 uptake carriers and MRP2 efflux transporter, as well as stable levels of MRP3, BCRP, and OATP1B1. However, most of these studies did not provide detailed information about patient stratification according to the Child–Pugh classification, and only El-Khateeb et al [ 9 ] specified that the analysis included five patients from the Child–Pugh class A and four subjects from class B (without detailed protein abundance results).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Wang et al [ 8 ] found an increase in MATE1 but decrease in BSEP, MRP2, NTCP, OATP1B3, OCT1, and P-gp, or no change in BCRP, MRP3, OATP1B1, and OATP2B1. A decrease in the protein abundance of MRP2 and OATP2B1 in hepatitis C cancer livers (in some samples, overlapped with alcoholic liver disease and nonalcoholic fatty liver disease) was also reported [ 9 ]. Our preliminary data in HCV livers mostly corroborate the abovementioned observations (decrease in BSEP, OCT1, OATP1B1, and OATP2B1 and stable levels of P-gp, MRP2, MRP3, MRP4, BCRP, NTCP, OCT3, OAT2, and OATP1B3 transporter proteins).…”

Section: Introductionmentioning

confidence: 98%

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Protein Abundance of Drug Transporters in Human Hepatitis C Livers

Droździk

Łapczuk-Romańska

Wenzel

et al. 2022

IJMS

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Transmembrane drug transport in hepatocytes is one of the major determinants of drug pharmacokinetics. In the present study, ABC transporters (P-gp, MRP1, MRP2, MRP3, MRP4, BCRP, and BSEP) and SLC transporters (MCT1, NTCP, OAT2, OATP1B1, OATP1B3, OATP2B1, OCT1, and OCT3) were quantified for protein abundance (LC-MS/MS) and mRNA levels (qRT-PCR) in hepatitis C virus (HCV)-infected liver samples from the Child–Pugh class A (n = 30), B (n = 21), and C (n = 7) patients. Protein levels of BSEP, MRP3, MCT1, OAT2, OATP1B3, and OCT3 were not significantly affected by HCV infection. P-gp, MRP1, BCRP, and OATP1B3 protein abundances were upregulated, whereas those of MRP2, MRP4, NTCP, OATP2B1, and OCT1 were downregulated in all HCV samples. The observed changes started to be seen in the Child–Pugh class A livers, i.e., upregulation of P-gp and MRP1 and downregulation of MRP2, MRP4, BCRP, and OATP1B3. In the case of NTCP, OATP2B1, and OCT1, a decrease in the protein levels was observed in the class B livers. In the class C livers, no other changes were noted than those in the class A and B patients. The results of the study demonstrate that drug transporter protein abundances are affected by the functional state of the liver in hepatitis C patients.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Protein Abundance of Drug Transporters in Human Hepatitis C Livers

Droździk

Łapczuk-Romańska

Wenzel

et al. 2022

IJMS

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“…Besides, CES1 is a vital drug metabolic enzyme in the liver that encodes about 1% of the total liver genomes ( 44 ). The liver inflammation or damage usually leads to alteration of liver drug-metabolizing enzymes, including CES1 ( 45 , 46 ). Consequently, the above results indicate that fluoride exposure affects the gene and protein expression levels of CES1 in vitro .…”

Section: Discussionmentioning

confidence: 99%

Fluorine impairs carboxylesterase 1-mediated hydrolysis of T-2 toxin and increases its chondrocyte toxicity

et al. 2022

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BackgroundT-2 toxin is recognized as one of the high-risk environmental factors for etiology and pathogenesis of Kashin-Beck disease (KBD). Previous evidence indicates decreased serum fluorine level in KBD patients. However, whether fluoride could regulate carboxylesterase 1 (CES1)-mediated T-2 toxin hydrolysis and alter its chondrocyte toxicity remains largely unknown.MethodsIn this study, in vitro hydrolytic kinetics were explored using recombinant human CES1. HPLC-MS/MS was used to quantitative determination of hydrolytic metabolites of T-2 toxin. HepG2 cells were treated with different concentration of sodium fluoride (NaF). qRT-PCR and western blot analysis were used to compare the mRNA and protein expression levels of CES1. C28/I2 cells were treated with T-2 toxin, HT-2 toxin, and neosolaniol (NEO), and then cell viability was determined by MTT assay, cell apoptosis was determined by Annexin V-FITC/PI, Hoechst 33258 staining, and cleaved caspase-3, and cell cycle was monitored by flow cytometry assay, CKD4 and CDK6.ResultsWe identified that recombinant human CES1 was involved in T-2 toxin hydrolysis to generate HT-2 toxin, but not NEO, and NaF repressed the formation of HT-2 toxin. Both mRNA and protein expression of CES1 were significantly down-regulated in a dose-dependent manner after NaF treatment in HepG2 cells. Moreover, we evaluated the chondrocyte toxicity of T-2 toxin and its hydrolytic metabolites. Results showed that T-2 toxin induced strongest cell apoptosis, followed by HT-2 toxin and NEO. The decreased the proportion of cells in G0/G1 phase was observed with the descending order of T-2 toxin, HT-2 toxin, and NEO.ConclusionsThis study reveals that CES1 is responsible for the hydrolysis of T-2 toxin, and that fluoride impairs CES1-mediated T-2 toxin detoxification to increase its chondrocyte toxicity. This study provides novel insight into understanding the relationship between fluoride and T-2 toxin in the etiology of KBD.

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“…Although outside the scope of this review, physiological changes caused by hepatic impairment can alter drug pharmacokinetics and DDI magnitudes, with the liver being the main metabolizing organ for the vast majority of small drugs. Hepatic enzyme activity, blood flow, functional liver mass, plasma protein concentration, liver transporter mRNA level, and activity in hepatic impairment conditions have been evaluated; 20 , 21 , 22 , 23 however, their cumulative impact on varying DDI mechanisms remains unclear. For example, enzyme inhibition has been reported to decrease in people with hepatic impairment, whereas enzyme induction is suggested to remain unchanged.…”

Section: Hepatic Impairmentmentioning

confidence: 99%

Drug–Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives

Cottura

Kinvig

Grañana-Castillo

et al. 2022

The Journal of Clinical Pharma

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Despite the advancement of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV), drug-drug interactions (DDIs) remain a relevant clinical issue for people living with HIV receiving ART. Antiretroviral (ARV) drugs can be victims and perpetrators of DDIs, and a detailed investigation during drug discovery and development is required to determine whether dose adjustments are necessary or coadministrations are contraindicated. Maintaining therapeutic ARV plasma concentrations is essential for successful ART, and changes resulting from potential DDIs could lead to toxicity, treatment failure, or the emergence of ARV-resistant HIV. The challenges surrounding DDI management are complex in special populations of people living with HIV,and often lack evidence-based guidance as a result of their underrepresentation in clinical investigations.Specifically, the prevalence of hepatic and renal impairment in people living with HIV are between five and 10 times greater than in people who are HIV-negative, with each condition constituting approximately 15% of non-AIDS-related mortality. Therapeutic strategies tend to revolve around the treatment of risk factors that lead to hepatic and renal impairment, such as hepatitis C, hepatitis B, hypertension, hyperlipidemia, and diabetes. These strategies result in a diverse range of potential DDIs with ART. The purpose of this review was 2-fold. First, to summarize current pharmacokinetic DDIs and their mechanisms between ARVs and co-medications used for the prevention and treatment of hepatic and renal impairment in people living with HIV. Second, to identify existing knowledge gaps surrounding DDIs related to these special populations and suggest areas and techniques to focus upon in future research efforts.

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Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment

Cited by 44 publications

References 60 publications

Protein Abundance of Drug Transporters in Human Hepatitis C Livers

Protein Abundance of Drug Transporters in Human Hepatitis C Livers

Fluorine impairs carboxylesterase 1-mediated hydrolysis of T-2 toxin and increases its chondrocyte toxicity

Drug–Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives

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