09/15/2021 - Miscellaneous
Péter Tátrai, Franciska Erdő, Gabriella Dörnyei, Péter Krajcsi
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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.
Keywords: drug-transporter interactions; hyperuricemia; hypouricemia; in vitro prediction; urate.
P.T. is an employee of Solvo Biotechnology, a company that specializes in the development and commercialization of transporter technology applications. P.K. was an employee of Solvo Biotechnology and the co-founder and co-owner of Habilitas LLC (Budapest, Hungary), a company that provides ADMETox consultation services. The companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.open_in_new Read the Source