Modulation of Urate Transport by Drugs
| Autor: | Péter Tátrai, Peter Krajcsi, Gabriella Dörnyei, Franciska Erdő |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Drug
Uricosuric media_common.quotation_subject Pharmaceutical Science Review hyperuricemia Pharmacology Urate transport 03 medical and health sciences Pharmacy and materia medica 0302 clinical medicine medicine in vitro prediction Hyperuricemia Hypouricemia 030304 developmental biology media_common 030203 arthritis & rheumatology 0303 health sciences business.industry Transporter medicine.disease Gout RS1-441 Drug development hypouricemia drug-transporter interactions urate business |
| Zdroj: | Pharmaceutics Pharmaceutics, Vol 13, Iss 899, p 899 (2021) |
| ISSN: | 1999-4923 |
| Popis: | 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 Cmax/IC50 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. |
| Databáze: | OpenAIRE |
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