Modulation of Urate Transport by Drugs
Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate dispo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/6/899 |
| _version_ | 1797529869136953344 |
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| author | Péter Tátrai Franciska Erdő Gabriella Dörnyei Péter Krajcsi |
| author_facet | Péter Tátrai Franciska Erdő Gabriella Dörnyei Péter Krajcsi |
| author_sort | Péter Tátrai |
| collection | DOAJ |
| description | Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. Methods: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like C<sub>max</sub>/IC<sub>50</sub> on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. Results: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. Conclusions: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1. |
| first_indexed | 2024-03-10T10:20:58Z |
| format | Article |
| id | doaj.art-e980c88b06d54b2087de909018b830b6 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T10:20:58Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e980c88b06d54b2087de909018b830b62023-11-22T00:28:47ZengMDPI AGPharmaceutics1999-49232021-06-0113689910.3390/pharmaceutics13060899Modulation of Urate Transport by DrugsPéter Tátrai0Franciska Erdő1Gabriella Dörnyei2Péter Krajcsi3Solvo Biotechnology, Science Park, Building B2, 4-20 Irinyi József utca, H-1117 Budapest, HungaryFaculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083 Budapest, HungaryDepartment of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, H-1088 Budapest, HungarySolvo Biotechnology, Science Park, Building B2, 4-20 Irinyi József utca, H-1117 Budapest, HungaryBackground: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. Methods: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like C<sub>max</sub>/IC<sub>50</sub> on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. Results: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. Conclusions: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1.https://www.mdpi.com/1999-4923/13/6/899uratedrug-transporter interactionsin vitro predictionhyperuricemiahypouricemia |
| spellingShingle | Péter Tátrai Franciska Erdő Gabriella Dörnyei Péter Krajcsi Modulation of Urate Transport by Drugs Pharmaceutics urate drug-transporter interactions in vitro prediction hyperuricemia hypouricemia |
| title | Modulation of Urate Transport by Drugs |
| title_full | Modulation of Urate Transport by Drugs |
| title_fullStr | Modulation of Urate Transport by Drugs |
| title_full_unstemmed | Modulation of Urate Transport by Drugs |
| title_short | Modulation of Urate Transport by Drugs |
| title_sort | modulation of urate transport by drugs |
| topic | urate drug-transporter interactions in vitro prediction hyperuricemia hypouricemia |
| url | https://www.mdpi.com/1999-4923/13/6/899 |
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