Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate, an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats

Futatsugi, Azusa; Masuo, Yusuke; Kato, Yukio

doi:10.1016/j.xphs.2021.02.011

Cited by 5 publications

(4 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Host gene pathway analysis showed OATs, which mediated transport of sodium and chloride ions across the airway lumen [ 39 , 40 ] are needed for viral replication. Probenecid is a chemical inhibitor of OAT transport, particularly OAT1 and OAT3 [ 17 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Murray

Bergeron

Jones

et al. 2022

Viruses

View full text Add to dashboard Cite

RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.

show abstract

Section: Discussionmentioning

confidence: 99%

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Murray

Bergeron

Jones

et al. 2022

Viruses

View full text Add to dashboard Cite

show abstract

“…Initially, we showed that probenecid treatment inhibited IAV replication by reducing OAT3 13 . Probenecid is a chemical inhibitor of OAT transport, particularly OAT1 and OAT3 19,35,36 . Host gene pathway analysis suggested that respiratory virus replication intersects OAT activity and that OATs may be needed for transport of viral constituents needed for viral replication using a similar process of OAT-mediated vectorial transport as for sodium and chloride ions across the airway lumen 37,38 .…”

Section: Discussionmentioning

confidence: 99%

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Murray¹,

Bergeron²,

Jones³

et al. 2022

Preprint

View full text Add to dashboard Cite

RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid prophylaxis or treatment inhibited RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and RSV B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.

show abstract

“…Previous investigators knocked out either Slc22a6 or Slc22a8 and used probenecid to inhibit the remaining transporter so as to mimic a double-knockout of Slc22a6/8 [20]. However, probenecid is a non-specific inhibitor [50,51], and may inhibit other transporters while inhibiting the OATs. In view of the difficulty of deleting both genes simultaneously, we constructed the rOAT1/rOAT3 double-knockout rat model by deletion of the majority of exons and a LOC102550957 gene between Slc22a6 and Slc22a8.…”

Section: Discussionmentioning

confidence: 99%

Construction and Evaluation of a Novel Organic Anion Transporter 1/3 CRISPR/Cas9 Double-Knockout Rat Model

et al. 2022

View full text Add to dashboard Cite

Background: Organic anion transporter 1 (OAT1) and OAT3 have an overlapping spectrum of substrates such that one can exert a compensatory effect when the other is dysfunctional. As a result, the knockout of either OAT1 or OAT3 is not reflected in a change in the excretion of organic anionic substrates. To date, only the mOAT1 and mOAT3 individual knockout mouse models have been available. Methods: In this study, we successfully generated a Slc22a6/Slc22a8 double-knockout (KO) rat model using CRISPR/Cas9 technology and evaluated its biological properties. Results: The double-knockout rat model did not expression mRNA for rOAT1 or rOAT3 in the kidneys. Consistently, the renal excretion of p-aminohippuric acid (PAH), the classical substrate of OAT1/OAT3, was substantially decreased in the Slc22a6/Slc22a8 double-knockout rats. The relative mRNA level of Slco4c1 was up-regulated in KO rats. No renal pathological phenotype was evident. The renal elimination of the organic anionic drug furosemide was nearly abolished in the Slc22a6/Slc22a8 knockout rats, but elimination of the organic cationic drug metformin was hardly affected. Conclusions: These results demonstrate that this rat model is a useful tool for investigating the functions of OAT1/OAT3 in metabolic diseases, drug metabolism and pharmacokinetics, and OATs-mediated drug interactions.

show abstract

Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate, an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats

Cited by 5 publications

References 56 publications

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Construction and Evaluation of a Novel Organic Anion Transporter 1/3 CRISPR/Cas9 Double-Knockout Rat Model

Contact Info

Product

Resources

About