N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

Müller, Fabian; Pontones, Constanza; Renner, Bertold; Mieth, Maren; Hoier, Eva; Auge, Daniel; Maas, Renke; Zolk, Oliver; Fromm, Martin F.

doi:10.1007/s00228-014-1770-2

Cited by 84 publications

(137 citation statements)

References 30 publications

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“…The [I] 1 /IC 50 values for ketoconazole and the sum of these values for itraconazole and its metabolites were .100-fold the cutoff value for OCT1. Although few reports show that the pharmacokinetics of OCT1 substrates are altered by OCT1 inhibitors (Cho et al, 2014;Müller et al, 2015), the high [I] 1 /IC 50 values for OCT1 reported in this work may be clinically relevant for some substrates of OCT1. For instance, verapamil was found to have an IC 50 value of 12.5 mM toward OCT1-mediated metformin transport, with an [I] 1 /IC 50 value of only 0.048 (Ahlin et al, 2011;University of Washington, 2015).…”

Section: Discussionmentioning

confidence: 67%

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Vermeer

Isringhausen

Ogilvie

et al. 2015

Drug Metabolism and Disposition

105

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Ketoconazole is a potent CYP3A4/5 inhibitor and, until recently, recommended by the Food and Drug Administration (FDA) and the European Medicines Agency as a strong CYP3A4/5 inhibitor in clinical drug-drug interaction (DDI) studies. Ketoconazole sporadically causes liver injury or adrenal insufficiency. Because of this, the FDA and European Medicines Agency recommended suspension of ketoconazole use in DDI studies in 2013. The FDA specifically recommended use of clarithromycin or itraconazole as alternative strong CYP3A4/5 inhibitors in clinical DDI studies, but many investigators have also used ritonavir as an alternative. Although the effects of these clinical CYP3A4/5 inhibitors on other CYPs are largely established, reports on the effects on the broad range of drug transporter activities are sparse. In this study, the inhibitory effects of ketoconazole, clarithromycin, ritonavir, and itraconazole (and its CYP3A4-inhibitory metabolites, hydroxy-, keto-, and N-desalkyl itraconazole) toward 13 drug transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, P-gp, BCRP, MRP2, MRP3, and BSEP) were systematically assessed in transporterexpressing HEK-293 cell lines or membrane vesicles. In vitro findings were translated into clinical context with the basic static model approaches outlined by the FDA in its 2012 draft guidance on DDIs. The results indicate that, like ketoconazole, the alternative clinical CYP3A4/5 inhibitors ritonavir, clarithromycin, and itraconazole each have unique transporter inhibition profiles. None of the alternatives to ketoconazole provided a clean inhibition profile toward the 13 drug transporters evaluated. The results provide guidance for the selection of clinical CYP3A4/5 inhibitors when transporters are potentially involved in a victim drug's pharmacokinetics.

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Section: Discussionmentioning

confidence: 67%

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Vermeer

Isringhausen

Ogilvie

et al. 2015

Drug Metabolism and Disposition

105

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“…From the literature we know that inhibitors of OCT and MATE can have a clinically relevant impact on the pharmacokinetics of concomitantly administered organic cations through reduction in their renal clearance (14,15,23). Known inhibitors are cimetidine for OCT2 (IC 50 of 110 M [24]) and MATE1/MATE2K (K i of 7 and 1 M, respectively [25]) as well as pyrimethamine for OCT2 (K i of 10 M [15]) and MATE1/ MATE2K (K i of 93 and 59 nM, respectively [15]).…”

Section: Discussionmentioning

confidence: 99%

Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Brake

Heuvel

Buaben

et al. 2016

Antimicrob Agents Chemother

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c It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEsT uberculosis (TB) remains a leading cause of morbidity and mortality in developing countries, claiming over a million lives annually (1). Treatment of TB requires long and intensive combination drug therapy, which can be complicated by the presence of concurrent diseases. The noncommunicable disease diabetes mellitus (DM) impacts TB with increasing magnitude (2, 3). At the moment, an estimated 15% of TB cases can be attributed to DM (3).Patients with DM have three times the risk of developing active TB compared to nondiabetics (3, 4), probably because of impaired host defenses. In addition, patients with TB and DM show a worse response to TB treatment than patients with TB alone and thus face a higher risk of TB treatment failure, relapse after cure, and death (5). The impact of DM will only increase further due to the rising prevalence of DM, especially in countries where TB is endemic. On the other hand, DM management is hampered by TB treatment. The TB drug rifampin possibly affects blood glucose itself and induces hyperglycemia by augmenting intestinal absorption of glucose or reducing insulin sensitivity (6, 7).Metformin is the first-choice antihyperglycemic drug to treat diabetes mellitus type 2. It is affordable and may be advantageous when combined with rifampin, as it is not metabolized. Metformin lowers both basal and postprandial plasma glucose (8) by inhibiting the production of hepatic glucose, reducing intestinal glucose absorption, and improving glucose uptake and utilization (9). Interestingly, recent data show that metformin also inhibits the intracellular growth of M. tuberculosis, restricts disease immunopathology, and augments the efficacy of conventional TB drugs. It has even been suggested as a possible adjunctive to standard TB treatment in nondiabetic TB patients (10).Metformin is eliminated unchanged into the urine with a halflife of approximately 5 h (11). Over a range of renal functions, the mean renal clearance in the population is approximately 4 times greater than that of creatinine, indicating that tubular secretion is the most important route of elimination (11). The oral absorption, hepatic uptake, and renal excretion of metformin are largely mediated by membrane transporters of the solute carrier (SLC) family, namely, organic cation transporters 1, 2, and 3 (OCT1, OCT2, and OCT3) and multidrug and toxin extrusion proteins 1 and 2K (MATE1 and MATE2K) ( Fig. 1) (11, 12). Genetic polymorphisms in these transporter genes explain at least some of the variability observed in metformin pharmacokinetics and drug responses (11). Furthermore, from studies of humans and mice, we know that inhibitors of OCTs and MATEs can alter the disposition of concomitantly administered organic cations, increasing

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“…18 Overall, these transporters mediate the cellular influx of structurally diverse compounds and greatly impact on the pharmacokinetics of drugs in body. Drugs and endogenous substances competing for SLC transporters have also been widely reported, [19][20][21] and can significantly impact on therapeutic outcomes and toxicities. To date, the interactions between SLC transporters and CQ or HCQ remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine and Hydroxychloroquine Are Novel Inhibitors of Human Organic Anion Transporting Polypeptide 1A2

Zhu

Chan

et al. 2016

Journal of Pharmaceutical Sciences

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N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction

Abstract: These data on the metformin-trimethoprim interaction support the potential utility of N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.

Cited by 84 publications

References 30 publications

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol

Chloroquine and Hydroxychloroquine Are Novel Inhibitors of Human Organic Anion Transporting Polypeptide 1A2

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