Article

N-Methylnicotinamide Is an Endogenous Probe for Evaluation of Drug–Drug Interactions Involving Multidrug and Toxin Extrusions (MATE1 and MATE2-K)

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 10/2012; 92(5):635-41. DOI: 10.1038/clpt.2012.138
Source: PubMed

ABSTRACT

Multidrug and toxin extrusion 1 (MATE1) and MATE2-K are H(+)/organic cation exchangers mediating the efflux of cationic drugs into the urine. N-methylnicotinamide (NMN) was found to be an endogenous substrate of MATE1 (Michaelis constant (K(m)) 301 ± 18 µmol/l) and MATE2-K (K(m) 422 ± 63 µmol/l) as well as a basolateral influx transporter, organic cation transporter 2 (K(m) 318 ± 29 µmol/l). A potent MATE inhibitor, pyrimethamine, competitively inhibited the uptake by MATE1 and MATE2-K with inhibition constant (K(i)) values of 83 ± 15 and 56 ± 11 nmol/l, respectively. The uptake of NMN by human kidney brush border membrane vesicles with a H(+) gradient was saturable (K(m) 360 ± 55 µmol/l) and completely inhibited by pyrimethamine. The renal clearance of endogenous NMN was 403 ± 61 in healthy male subjects, and it was significantly decreased to 119 ± 16 ml/min/kg by an oral dose of pyrimethamine (50 mg). These results support the utility of NMN as an endogenous in vivo probe for investigating MATE1 and MATE2-K in humans.

0 Followers
 · 
25 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Therapy with two or more drugs is more the rule than the exception, particularly in aging societies. Drug-drug interactions are frequently undesirable and may lead to increased toxicity and mortality. Inhibition of transporters is one major mechanism underlying drug-drug interactions. The myriad of potential drug combinations makes it very challenging to predict drug-drug interactions. This Commentary discusses potential advantages and limitations of endogenous compounds for predicting transporter-mediated drug-drug interactions.
    No preview · Article · Nov 2012 · Clinical Pharmacology &#38 Therapeutics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Drug transporters play indispensable roles in the disposition of drugs in the body; e.g., in hepatic and renal eliminations, intestinal absorption, and in transport across active barriers, and consequently, in the response to drugs. Importance of the solute carrier family, such as OATP/SLCO, OCT/SLC22, OAT/SLC22, and MATE/SLC47, and the ATP-binding cassette transporters, such as P-glycoprotein/ABCB1, MRPs/ABCC, and BCRP/ABCG2, are well recognized in drug discovery and clinical situations. To date, it is however a great challenge to identify in vivo probe substrates and inhibitors applicable for investigating the impact of drug transporters in humans. This chapter has summarized the relevant clinical drug–drug interaction and pharmagenomic studies on drug transporters in humans, as well as some in vitro studies on transporters, in order to suggest applicable probe substrates and inhibitors for drug transporters. In addition to the drugs at the market, some endogenous and food-derived metabolites are probes for drug transporters. This chapter also highlights the impact of drug transporters on such compounds.
    No preview · Chapter · Jan 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation.
    No preview · Article · Apr 2013 · Pharmacological reviews
Show more