Dicloxacillin and Flucloxacillin Inhibit Hepatic Uptake Transporters-In Vitro In...

연구 요약

Dicloxacillin and Flucloxacillin Inhibit Hepatic Uptake Transporters-In Vitro Investigations and Physiologically Based Pharmacokinetic Modeling.

Clinical and translational science 학술지에 발표된 이 연구는 Sjöstedt N, Amaeze OU, van den Heuvel JJMW 외 연구팀이 수행하였습니다.

이 연구는 'Dicloxacillin and Flucloxacillin Inhibit Hepatic Uptake Transporters-In Vitro Investigations and Physiologically Based Pharmacokinetic Modeling.'에 대한 과학적 분석을 제공합니다.

핵심 내용

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 and 31 μM (OATP1B1) and 6.7 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.

일반인을 위한 해석

구체적인 실천 사항은 담당 의사 또는 약사와 상담하시기 바랍니다.

실천 사항

• 현재 복용 중인 약물이나 영양제에 대해 궁금한 점이 있다면 담당 의사 또는 약사와 상담하시기 바랍니다
• 약물이나 영양제의 용법·용량을 임의로 변경하지 마세요
• 이상 반응이 나타나면 즉시 전문가에게 문의하세요

의사/약사의 전문적 판단을 대체하지 않습니다 (PMID: 41630535)

📄 [전문 보기 (Markdown)](fulltext/41630535-dicloxacillin-and-flucloxacillin-inhibit-hepatic-uptake-tran.md)