TY - JOUR T1 - Elucidation of N1-methyladenosine as a potential surrogate biomarker for drug interaction studies involving renal organic cation transporters JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.087262 SP - dmd.119.087262 AU - Takeshi Miyake AU - Tadahaya Mizuno AU - Issey Takehara AU - Tatsuki Mochizuki AU - Miyuki Kimura AU - Shunji Matsuki AU - Shin Irie AU - Nobuaki Watanabe AU - Yukio Kato AU - Ichiro Ieiri AU - Kazuya Maeda AU - Osamu Ando AU - Hiroyuki Kusuhara Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/09/11/dmd.119.087262.abstract N2 - Endogenous substrates are emerging biomarkers for drug transporters, which serve as surrogate probes in drug-drug interaction (DDI) studies. In this study, the results of metabolome analysis using wild-type and Oct1/2 double knockout mice suggested that N1-methyladenosine (m1A) was a novel OCT2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2 and MATE2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 ± 4.9 mL/min/kg) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 ± 2.6 and 24.3 ± 0.6 mL/min/kg, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of DX-619 in cynomolgus monkeys resulted in the elevation of the area under the curve of m1A (1.72-fold) as well as metformin (2.18-fold). The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. The renal clearance of m1A in young (21-45 years old) and older (65-79 years old) volunteers (244 ± 58 and 169 ± 22 mL/min/kg, respectively) was about 2-fold higher than creatinine clearance. The renal clearance of m1A and creatinine was 31% and 17% smaller in older than young volunteers. Thus, m1A could be a surrogate probe for the evaluation of DDIs involving OCT2/MATE2-K.SIGNIFICANCE STATEMENT Endogenous substrates can serve as surrogate probes for clinical drug-drug interaction studies involving drug transporters or enzymes. N1-methyladenosine (m1A) was found as the novel substrate of renal cationic drug transporters, OCT2 and MATE2-K. m1A was revealed to have some advantages compared to other OCT2/MATEs substrate, creatinine and N1-methylnicotinamide. The genetic or chemical impairment of OCT2 or MATE2-K caused significant increase of plasma m1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. Plasma m1A concentration profile showed low diurnal and interindividual variation, and m1A undergoes renal tubular secretion in healthy volunteers. Thus, m1A could be a biomarker for quantitative assessment of OCT2/MATE2-K-mediated drug-drug interaction risks of drugs. ER -