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

Marie-emilie Willemin, Thomas K. Van Der Made, Ils Pijpers, Lieve Dillen, Annett Kunze, Sophie Jonkers, Kathleen Steemans, An Tuytelaars, Frank Jacobs, Mario Monshouwer, Daniel Scotcher, Amin Rostami-hodjegan, Aleksandra Galetin, Jan Snoeys

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Endogenous biomarkers are promising tools to assess transporter-mediated drug–drug interactions early in humans.

We 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.

PDA 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.

The 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.
Original languageEnglish
JournalClinical Pharmacokinetics
Early online date10 Apr 2021
Publication statusPublished - 10 Apr 2021


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