Genetic polymorphisms of human hepatic OATPs: functional consequences and effect on drug pharmacokinetics

Nie, Yingmin; Yang, Jingjie; Liu, Shuai; Sun, Ruiqi; Chen, Huihui; Long, Nan; Jiang, Rui; Gui, Chunshan

doi:10.1080/00498254.2019.1629043

Cited by 19 publications

(20 citation statements)

References 205 publications

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“…So far, studies on the genetic variations of OATP2B1 are relatively few and mainly focus on two common variants, namely, c.935G > A (p.R312Q) and c.1457C > T (p.S486F). 15 It was reported that variants c.935G > A and c.1457C > T would decrease OATP2B1's function 16,17 and alter the pharmacokinetic properties or response of its substrate drugs such as fexofenadine and rosuvastatin. 8,18 However, in the present study significant reduction of the function of variants c.935G > A (p.R312Q) and c.1457C > T (p.S486F) was not observed (Figure 1).…”

Section: ■ Discussionmentioning

confidence: 99%

“…So far, most genetic variation studies on OATPs are focusing on two liver-specific OATPs, namely, OATP1B1 and 1B3. 15 Studies on the genetic variations of SLCO2B1 are relatively few and several nonsynonymous SNVs have been reported including SLCO2B1 c.935G > A (p.R312Q) and c.1457C > T (p.S486F). 15 In vitro functional studies showed that variants c.935G > A and c.1457C > T significantly decreased OATP2B1's transport activity.…”

Section: ■ Introductionmentioning

confidence: 99%

“…15 Studies on the genetic variations of SLCO2B1 are relatively few and several nonsynonymous SNVs have been reported including SLCO2B1 c.935G > A (p.R312Q) and c.1457C > T (p.S486F). 15 In vitro functional studies showed that variants c.935G > A and c.1457C > T significantly decreased OATP2B1's transport activity. 16,17 In vivo pharmacokinetic studies indicated that SLCO2B1 c.935G > A could reduce the lipid-lowering effect of rosuvastatin and c.1457C > T resulted in a significant decrease of the area under the plasma concentration−time curve (AUC) of fexofenadine.…”

Section: ■ Introductionmentioning

confidence: 99%

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Functional Characterization Reveals the Significance of Rare Coding Variations in Human Organic Anion Transporting Polypeptide 2B1 (SLCO2B1)

et al. 2020

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The organic anion transporting polypeptide 2B1 (OATP2B1), which is encoded by the SLCO2B1 gene, plays important roles in the absorption and disposition of its substrate drugs. Nonsynonymous variations of SLCO2B1 change its amino acid sequence and may alter its function. However, so far, very few genetic variants of SLCO2B1 have been functionally characterized.In the present study, first of all, 14 nonsynonymous single nucleotide variants (SNVs) of SLCO2B1 have been identified from the dbSNP database. Then, human embryonic kidney (HEK293) cells were employed as the expression system and functional studies were carried out for these 14 SNVs using substrates 4′,5′-dibromofluorescein (DBF), estrone-3-sulfate (E3S), atorvastatin, and rosuvastatin. Our results showed that four nonsynonymous rare variants, namely, SLCO2B1 c.332G > A (p.R111Q), c.1184C > A (p.P395H), c.1624G > A (p.V542M), and c.1998C > A (p.F666L), have great effect on the function of OATP2B1. Surface biotinylation and immunoblot analysis indicated that the variant c.1184C > A (p.P395H) almost completely disrupted OATP2B1's expression on the plasma membrane. According to the three-dimensional structural model of OATP2B1 we developed, these four mutated residues are not located at the substrate binding region of OATP2B1. Their significant effect on the function of OATP2B1 could probably be attributed to jeopardizing OATP2B1's surface expression as exemplified by c.1184C > A (p.P395H), altering the transporter's overall structure and affecting its interactions with other proteins or the lipid bilayer. Taken together, our results demonstrated that rare coding variants could have a great impact on the function and expression of OATP2B1.

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Section: ■ Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Functional Characterization Reveals the Significance of Rare Coding Variations in Human Organic Anion Transporting Polypeptide 2B1 (SLCO2B1)

et al. 2020

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“…Transporters too have an important role in drug fate within the human body. Their interplay, along with pharmacogenetic variability, can change drug metabolism and reuptake of substances, prolonging drug bioavailability and increasing the risk of ADRs ( 43 , 44 )…”

Section: Discussion and Review Of Drug-drug-gene Interactionsmentioning

confidence: 99%

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review

Božina

Ganoci

Šimičević

et al. 2021

Archives of Industrial Hygiene and Toxicology

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Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.

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“…The final version may differ from this version. The variability data of DTs are essential for the determination of the inter-individual variations in drug response and side effects (Yee et al, 2018;Nie et al, 2020). Besides the variabilities in exogenous regulation and genetic polymorphism explicitly discussed in the 2.1 section, two additional aspects of variability (varied protein abundances & diverse epigenetic regulation) should be considered for DTs, due to their importance in bridging the preclinical investigations with clinical trials (Durmus et al, 2015) and leading to multidrug resistance in complex disease (Zhou et al, 2020), respectively.…”

Section: Diverse Data Illustrating Various Aspects Of Dt Variabilitymentioning

confidence: 99%

Feature, Function, and Information of Drug Transporter–Related Databases

Yin¹,

Li²,

et al. 2021

Drug Metab Dispos

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With the rapid progress in pharmaceutical experiments and clinical investigations, extensive knowledge of drug transporters (DTs) has accumulated, which is valuable data for the understanding of drug metabolism and disposition. However, such data is largely dispersed in the literature, which hampers its utility and significantly limits its possibility for comprehensive analysis. A variety of databases have, therefore, been constructed to provide DT-related data, and they were reviewed in this study. First, several knowledge bases providing data regarding clinically important drugs and their corresponding transporters were discussed, which constituted the most important resources of DT-centered data. Second, some databases describing the general transporters and their functional families were reviewed. Third, various databases offering transporter information as part of their entire data collection were described.Finally, customized database functions that are available to facilitate DT-related research were discussed. This review provided an overview of the whole collection of DT-related databases, which might facilitate research on precision medicine and rational drug use. Significant StatementA collection of well-established databases related to DTs were comprehensively reviewed, which were organized according to their importance in drug ADME research. These databases could collectively contribute to the research on rational drug use.

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Genetic polymorphisms of human hepatic OATPs: functional consequences and effect on drug pharmacokinetics

Cited by 19 publications

References 205 publications

Functional Characterization Reveals the Significance of Rare Coding Variations in Human Organic Anion Transporting Polypeptide 2B1 (SLCO2B1)

Functional Characterization Reveals the Significance of Rare Coding Variations in Human Organic Anion Transporting Polypeptide 2B1 (SLCO2B1)

Drug-drug-gene interactions as mediators of adverse drug reactions to diclofenac and statins: a case report and literature review

Feature, Function, and Information of Drug Transporter–Related Databases

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