Dicloxacillin and flucloxacillin inhibit hepatic uptake transporters -in vitro investigations and physiologically based pharmacokinetic modelling.

Authors

Noora Sjöstedt, Ogochukwu U Amaeze, Jeroen Jmw van den Heuvel, Tore B Stage, Jan B Koenderink, Nina Isoherranen, Heidi Kidron, Erkka Järvinen

Published in

bioRxiv : the preprint server for biology. Oct 22, 2025. Epub Oct 22, 2025.

Abstract

Dicloxacillin and flucloxacillin are β-lactamase-resistant penicillin antibiotics that have been in clinical use for over 50 years. While both antibiotics are known to induce cytochrome P450 enzymes, there is limited information available regarding their interactions with drug transporters. Here, we investigated the in vitro transport and inhibition of hepatic organic anion transporting polypeptides (OATPs) and renal organic anion transporters (OATs) by these antibiotics in recombinant transporter overexpressing HEK293 cells. We also investigated the transport of these antibiotics by efflux transporters, as well as their inhibition of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) using a HEK293 membrane vesicle transport assay. Dicloxacillin and flucloxacillin inhibited rosuvastatin transport by OATP1B1, OATP1B3 and OATP2B1, and the inhibition was strongest for OATP1Bs with IC₅₀ values of 3.9 μM and 31 μM (OATP1B1) and 6.7 μM and 21 μM (OATP1B3) for dicloxacillin and flucloxacillin, respectively. Both antibiotics also inhibited BCRP-mediated rosuvastatin transport with IC₅₀ values of 166 μM (dicloxacillin) and 379 μM (flucloxacillin), while P-gp-mediated transport of N-methyl-quinidine was inhibited to a lesser extent. All OATPs and OATs transported dicloxacillin and flucloxacillin. Static model predictions indicated that the inhibition of OATPs, BCRP and P-glycoprotein by both compounds may be clinically relevant. We further developed and verified physiologically based pharmacokinetic (PBPK) models for dicloxacillin and flucloxacillin. PBPK model simulations predicted no major change in rosuvastatin, a substrate for OATPs and BCRP, pharmacokinetics, when co-administered with dicloxacillin or flucloxacillin. Simulations with dicloxacillin and P-gp substrates dabigatran or digoxin also predicted limited inhibition of P-gp transport.

PMID:
41278897
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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