Dillen, Lieve

Galetin, Aleksandra

Jacobs, Frank

Jonkers, Sophie

Kunze, Annett

Monshouwer, Mario

Pijpers, Ils

Rostami-hodjegan, Amin

Scotcher, Daniel

Snoeys, Jan

Steemans, Kathleen

Tuytelaars, An

Van Der Made, Thomas K.

Willemin, Marie-emilie

English

BackgroundEndogenous biomarkers are promising tools to assess transporter-mediated drug–drug interactions early in humans.MethodsWe evaluated on a common and validated in vitro system the selectivity of 4-pyridoxic acid (PDA), homovanillic acid (HVA), glycochenodeoxycholate-3-sulphate (GCDCA-S) and taurine towards different renal transporters, including multidrug resistance-associated protein, and assessed the in vivo biomarker sensitivity towards the strong organic anion transporter (OAT) inhibitor probenecid at 500 mg every 6 h to reach close to complete OAT inhibition.ResultsPDA and HVA were substrates of the OAT1/2/3, OAT4 (PDA only) and multidrug resistance-associated protein 4; GCDCA-S was more selective, having affinity only towards OAT3 and multidrug resistance-associated protein 2. Taurine was not a substrate of any of the investigated transporters under the in vitro conditions tested. Plasma exposure of PDA and HVA significantly increased and the renal clearance of GCDCA-S, PDA and HVA decreased; the magnitude of these changes was comparable to those of known clinical OAT probe substrates. PDA and GCDCA-S were the most promising endogenous biomarkers of the OAT pathway activity: PDA plasma exposure was the most sensitive to probenecid inhibition, and, in contrast, GCDCA-S was the most sensitive OAT biomarker based on renal clearance, with higher selectivity towards the OAT3 transporter.ConclusionsThe current findings illustrate a clear benefit of measuring PDA plasma exposure during phase I studies when a clinical drug candidate is suspected to be an OAT inhibitor based on in vitro data. Subsequently, combined monitoring of PDA and GCDCA-S in both urine and plasma is recommended to tease out the involvement of OAT1/3 in the inhibition interaction

The University of Manchester - Institutional Repository

Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug–Drug Interactions

https://pure.manchester.ac.uk/ws/files/191036411/Willemin_ME_et_al._Author_Accepted_Manuscript_clean.pdf

Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug–Drug Interactions

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The University of Manchester - Institutional Repository