Efavirenz reduces renal excretion of lamivudine in rats by inhibiting organic cation transporters (OCT, Oct) and multidrug and toxin extrusion proteins (MATE, Mate)

Abstract

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor used in first-line combination antiretroviral therapy (cART). It is usually administered with nucleoside reverse transcriptase inhibitors (NRTI), many of which are substrates of OCT uptake solute carriers (SLC22A) and MATE (SLC47A), P-gp (MDR1, ABCB1), BCRP (ABCG2), or MRP2 (ABCC2) efflux transporters. The aim of this study was to evaluate the inhibitory potential of efavirenz towards these transporters and investigate its effects on the pharmacokinetics and tissue distribution of a known Oct/Mate substrate, lamivudine, in rats. Accumulation and transport assays showed that efavirenz inhibits the uptake of metformin by OCT1-, OCT2- and MATE1-expressing MDCK cells and reduces transcellular transport of lamivudine across OCT1/OCT2- and MATE1-expressing MDCK monolayers. Only negligible inhibition of MATE2-K was observed in HEK-MATE2-K cells. Efavirenz also reduced the efflux of calcein from MDCK-MRP2 cells, but had a rather weak inhibitory effect on Hoechst 33342 accumulation in MDCK-MDR1 and MDCK-BCRP cells. An in vivo pharmacokinetic interaction study in male Wistar rats revealed that intravenous injection of efavirenz or the control Oct/Mate inhibitor cimetidine significantly reduced the recovery of lamivudine in urine and greatly increased lamivudine retention in the renal tissue. Co-administration with efavirenz or cimetidine also increased the AUC0-∞ value and reduced total body clearance of lamivudine. These data suggest that efavirenz is a potent inhibitor of OCT/Oct and MATE/Mate transporters. Consequently, it can engage in drug-drug interactions that reduce renal excretion of co-administered substrates and enhance their retention in the kidneys, potentially compromising therapeutic safety.

Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models

“…In both cases, the presence of 10 µM efavirenz in the basolateral compartment reduces the basolateral to apical transport in all single-and doubletransfected cell lines, except in the MDCK control cells. The intracellular accumulation of both substrates was decreased in the MDCK-OCT1 cells but increased in the MDCK-MATE1 cells, confirming the potential of efavirenz as an in vitro inhibitor of both transport proteins (Ceckova et al, 2018). Li et al (Li et al, 2018) addressed a potential drug-drug interaction between metformin and nuciferine, the active ingredient of lotus leafs (Folium Nelumbinis).…”

“…The fact, that mitoxantrone inhibition led to an increase of the intracellular accumulation of lamivudine, underlines the importance of MATE1 on the transport of lamivudine. Later, Ceckova et al (Ceckova et al, 2018) used the MDCK-OCT1-MATE1 double-transfectant to study the inhibition of the transcellular transport of 2 nM MPP + and 10 nM lamivudine by adding efavirenz. In both cases, the presence of 10 µM efavirenz in the basolateral compartment reduces the basolateral to apical transport in all single-and doubletransfected cell lines, except in the MDCK control cells.…”

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2

“…To further investigate the role of MRP2, accumulation experiments in MRP2-MDCK cells were performed as previously described [ 28 – 31 ]. Briefly, cells were seeded at a density of 2 × 10 5 cells/well on a 24-well plate.…”

Drug-Drug Interactions at Organic Cation Transporter 1

“…Efavirenz has been demonstrated as an inhibitor of OCT1 by using hOCT1-overexpressing MDCK and KCL2 cells. The drug could inhibit the cellular transport and intracellular accumulation of lamivudine ( Moss et al, 2015 ; Ceckova et al, 2018 ). The possible DDIs should be considered when co-administering efavirenz to HIV patients with other drugs.…”