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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. [ABSTRACT FROM AUTHOR]

• Perchlorates in environment rise concerns, sensitive determination techniques needed. • Analysis and critical evaluation of published electrochemical perchlorate sensors. • Voltammetric methods superior over „classical" potentiometric ISE. • Electrochemical impedance and capacitance sensors - the lowest detection limit. • Capability of electrochemical sensors to replace ion/mass chromatography shown. Growing concerns about adverse effects of perchlorate (ClO 4 −) together with its relatively frequent occurrence in the environment demand sensitive analytical methods. It is also anticipated that ClO 4 − sensors will find their application in future extra-terrestrial missions. Ion chromatography (IC) and mass spectroscopy (MS) provide sufficiently low detection limit (LOD) but lack transportability and field analysis possibility that are provided by most electrochemical analytical methods. On the other side, commercially available potentiometric ion-selective electrodes (ISEs) cannot compete with IC or MS in terms of sensitivity. To answer the question whether (and how) such drawback can be overcome, in this paper electrochemical methods of ClO 4 − determination are introduced and evaluated. Starting with potentiometric ISEs which can theoretically reach LOD suitable for assessment of WHO-set limits of ClO 4 −, it is further shown that ISEs operating in voltammetric mode are superior in terms of sensitivity. Next section covers impedimetric and capacitance ClO 4 − sensors, concluding that they can reach detection limits of IC or MS while retaining their advantages. In further sections related issues are discussed including biosensing or direct electrochemical reduction of perchlorate as well as diversity of (nano)materials applicable for perchlorate sensors preparation. This critical review thus shows that electrochemical ClO 4 − sensors can reach sensitivity of standard methods while retaining their portability and ease of operation. [ABSTRACT FROM AUTHOR]

1. Emtricitabine is a nucleoside reverse transcriptase inhibitor used in combination antiretroviral therapy of HIV (cART). Although active transport mechanisms are believed to mediate tubular secretion of the drug into urine, the responsible transporter and its potential to cause pharmacokinetic drug--drug interactions (DDI) has not been identified so far. The aim of this study was to investigate whether drug transporters P-gp (ABCB1), BCRP (ABCG2), MRP2 (ABCC2), OCT1 (SLC22A1), OCT2 (SLC22A2) or MATE1 (SLC47A1) can mediate active transcellular transfer of emtricitabine. 2. We employed transport assays in polarized monolayers of MDCK cells stably expressing P-gp, BCRP, MRP2, OCT1, OCT2 and/or MATE1. Among the transporters studied only MATE1 accelerated basal-to-apical transport of emtricitabine over a wide range of concentrations (6 nM to 1 mM). The transport was enhanced by an oppositely directed pH gradient and significantly reduced (p < 0.001) at low temperature in MDCK-MATE1, MDCK-OCT1/MATE1 and MDCK-OCT2/MATE1 cells. Co-administration of cimetidine or ritonavir decreased MATE1-mediated transport of emtricitabine by up to 42 and 39%, respectively (p < 0.01) and augmented intracellular accumulation of emtricitabine (p < 0.05). 3. We demonstrate emtricitabine as a substrate of MATE1 and suggest that MATE1 might cause DDI between emtricitabine and other co-administrated drugs including antiretrovirals. [ABSTRACT FROM AUTHOR]

Efavirenz is an antiretroviral drug used in the treatment of HIV-positive patients. A simple, fast and sensitive high-performance liquid chromatography (HPLC) method was developed in order to determine efavirenz in three types of samples provided from pharmacokinetic studies. The analysis took 5 min and was performed using a C18 analytical column (Discovery HS C18, 150 × 4.6 mm, particle size of 5 μm) in isocratic mode with a mobile phase containing acetonitrile and water (65:35, v/v), a flow rate of 1.6 mL min −1 , a sample volume of 10 μL and UV detection at 245 nm. Three different sample matrices (Opti-MEM medium, Krebs perfusion liquid and tissue lysate) and their treatment (dilution, SPE) were considered. The validated method was applied for the analysis of 805 real samples arising from in vitro transcellular transport assays and in vivo organ perfusion experiments in order to evaluate the interaction of efavirenz with ATP-dependent drug efflux transporters. The lack of interaction of efavirenz with ABCB1, ABCG2 and ABCC2 transporters as well as technical aspects of this analysis, including the adhesion of efavirenz to the plastic materials and the stability of the drug during different tissue lysis approaches are discussed. [ABSTRACT FROM AUTHOR]