Proguanil and cycloguanil are organic cation transporter and multidrug and toxin extrusion substrates

Abstract

BackgroundMalaria, HIV/AIDS, and tuberculosis endemic areas show considerable geographical overlap, leading to incidence of co-infections. This requires treatment with multiple drugs, potentially causing adverse drug–drug interactions (DDIs). As anti-malarials are generally positively charged at physiological pH, they are likely to interact with human organic cation transporters 1 and 2 (OCT1 and OCT2). These transporters are involved in the uptake of drugs into hepatocytes and proximal tubule cells for subsequent metabolic conversion or elimination. This efflux of cationic drugs from hepatocytes and proximal tubule cells into bile and urine can be mediated by multidrug and toxin extrusion 1 and 2-K (MATE1 and MATE2-K) transporters, respectively.MethodsHere, the interaction of anti-malarials with these transporters was studied in order to predict potential DDIs. Using baculovirus-transduced HEK293 cells transiently expressing human OCT1, OCT2, MATE1 and MATE2K uptake and inhibition was studied by a range of anti-malarials.ResultsAmodiaquine, proguanil, pyrimethamine and quinine were the most potent inhibitors of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP) transport, a known substrate of OCT1/2, resulting in half maximal inhibitory concentrations (IC50) of 11, 13, 1.6, and 3.4 µM, respectively. Only quinine had a drug–drug index higher than the cut-off value of 0.1 for OCT2, therefore, in vivo pharmacokinetic studies focusing on DDIs involving this compound and other OCT2-interacting drugs are warranted. Furthermore, proguanil appeared to be a substrate of OCT1 and OCT2 with affinities of 8.1 and 9.0 µM, respectively. Additionally, MATE1 and MATE2-K were identified as putative transport proteins for proguanil. Finally, its metabolite cycloguanil was also identified as an OCT1, OCT2, MATE1 and MATE2-K substrate.ConclusionAnti-malarials can reduce OCT1 and OCT2 transport activity in vitro. Furthermore, proguanil and cycloguanil were found to be substrates of OCT1, OCT2, MATE1 and MATE2-K, highlighting the importance of these transporters in distribution and excretion. As these compounds shares substrate overlap with metformin DDIs can be anticipated during concurrent treatment.

OCT1 Deficiency Affects Hepatocellular Concentrations and Pharmacokinetics of Cycloguanil, the Active Metabolite of the Antimalarial Drug Proguanil

“…Regarding potential drug-drug interactions, a recently published in vitro study suggested that a number of antimalarial drugs may inhibit OCT1 uptake. 43 No clinically relevant drug-drug interaction may be expected with the co-administered atovaquone, but the proguanil-quinine combination, for example, may not be advisable according to these data.…”

Completing the Enalaprilat Excretion Pathway—Renal Handling by the Proximal Tubule

“…All relevant transporters showed uptake of their model substrate. For OAT1, OAT3, OCT2, MATE1, MATE2k, MRP2, MRP4, P-gp, and BCRP, this has been previously described [ 15 , 17 , 18 , 19 ]. OAT2, OAT4, PEPT1, PEPT2, URAT1, OCTN1, and OCTN2 all showed a significant transport ratio compared to control cells and were thus also considered suitable for testing enalaprilat specificity ( Supplementary Figure S1 ).…”

“…For MRP2, MRP4, P-gp, and BCRP, this was described by Lempers et al [ 18 ]. MATE1, MATE2k, and OCT2 specificity were tested by Van der Velden et al [ 19 ] ( Table 1 ). OAT2 and OAT4 were tested using [ 14 C]-PAH, PEPT1 and PEPT2 using [ 3 H]-Gly-Sar, URAT1 using urate, and OCTN1 and OCTN2 using [ 14 C]-Carnitine ( Supplementary Figure S1 ).…”

“…This method of co-transduction was previously described by van der Velden et al as a valid method to identify efflux transporter specificity. In their article, they demonstrated a statistically significant decrease in the uptake of the OCT1 substrate proguanil in cells co-transduced with OCT1 and MATE-2k, compared to OCT1 alone [ 19 ]. Quantification of enalaprilat: Enalaprilat was quantified with LC-MS/MS, using an Acquity UPLC (Waters, Milford, MA, USA) coupled to a Xevo TQ-S (Waters) triple quadropole mass spectrometer.…”

Genetic Heterogeneity of SLC22 Family of Transporters in Drug Disposition

“…OCT2 also accounts for the uptake of this drug by proximal tubular cells from the bloodstream [ 47 ]. The anti-malarial drugs proguanil and cycloguanil, the anti-retroviral entecavir, and anti-hypertensive atenolol are also substrates of OCT2, while amodiaquine, pyrimethamine and quinine are inhibitors of this transporter [ 48 , 49 , 50 ]. Cimetidine, anti-arrhythmic drugs quinidine and procainamide, and the anti-retroviral amantadine, are also inhibitors of both OCT2 and OCT1 [ 51 ].…”