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BioAssay: AID 681160

TP_TRANSPORTER: inhibition of Adefovir uptake in OAT1-expressing CHO cells

Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy with adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes in laboratory markers of renal tubular functions that are reversible upon drug discontinuation. It has been recently shown that more ..
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 Tested Compounds
 Tested Compounds
All(12)
 
 
Unspecified(12)
 
 
 Tested Substances
 Tested Substances
All(12)
 
 
Unspecified(12)
 
 
 Related BioAssays
 Related BioAssays
AID: 681160
Data Source: ChEMBL (838299)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Other
BioAssay Version:
Deposit Date: 2013-05-16
Modify Date: 2014-05-27

Data Table ( Complete ):           View All Data
Target
Sequence: RecName: Full=Solute carrier family 22 member 6; AltName: Full=Organic anion transporter 1; Short=hOAT1; AltName: Full=PAH transporter; Short=hPAHT; AltName: Full=Renal organic anion transporter 1; Short=hROAT1
Description ..   
Protein Family: MFS
Comment ..   

Gene:SLC22A6          More BioActivity Data..
Tested Compounds:
Description:
Title: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1.

Abstract: Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy with adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes in laboratory markers of renal tubular functions that are reversible upon drug discontinuation. It has been recently shown that adefovir is efficiently transported by the human renal organic anion transporter 1 (hOAT1), a membrane transport protein localized in the kidney, that presumably mediates the accumulation of adefovir in renal proximal tubules. In an effort to look for novel inhibitors of this transport process, we used a cell line stably expressing hOAT1 to demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) efficiently inhibit hOAT1-specific transport of adefovir at clinically relevant concentrations. Diflunisal, ketoprofen, flurbiprofen, indomethacin, naproxen, and ibuprofen were equally or more effective (IC(50) = 0.85-8 microM) than probenecid or betamipron, two known potent inhibitors of hOAT1 (IC(50) = 8 and 6 microM, respectively) with in vivo nephroprotective effects. Importantly, NSAIDs significantly reduced the shift in adefovir cytotoxicity observed upon hOAT1 expression with ketoprofen and naproxen being 2- to 3-times more effective than probenecid. Transport experiments with [(3)H]ketoprofen and [(3)H]ibuprofen revealed that NSAIDs themselves were not efficiently transported by hOAT1. None of the NSAIDs tested showed any interference with the anti-HIV activity of adefovir. In conclusion, these observations suggest that NSAIDs may reduce or delay the emergence of adefovir nephrotoxicity.
Categorized Comment
Assay Type: Functional

Assay Data Source: TP-search Transporter Database

Assay Test Type: In vitro

BAO: Assay Format: cell-based format

Assay Cell Type: CHO

Target Type: Target is a single protein chain

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
2IC50 activity commentIC50 activity commentString
3IC50 standard flagIC50 standard flagInteger
4IC50 qualifierIC50 qualifierString
5IC50 published valueIC50 published valueFloatμM
6IC50 standard valueIC50 standard valueFloatnM
7IC50 data validityIC50 data validityString
8IC50 binding domainsIC50 binding domainsString

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View All Data
Classification
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