Elucidation of N1-methyladenosine as a potential surrogate biomarker for drug interaction studies involving renal organic cation transporters

Takeshi Miyake, Tadahaya Mizuno, Issey Takehara, Tatsuki Mochizuki, Miyuki Kimura, Shunji Matsuki, Shin Irie, Nobuaki Watanabe, Yukio Kato, Ichiro Ieiri, Kazuya Maeda, Osamu Ando, Hiroyuki Kusuhara

Research output: Contribution to journalArticle

Abstract

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 organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 6 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 6 2.6 and 24.3 6 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2- fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid 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 ofm1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 658 and 1696 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger 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. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasmam1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.

Original languageEnglish
Pages (from-to)1270-1280
Number of pages11
JournalDrug Metabolism and Disposition
Volume47
Issue number11
DOIs
Publication statusPublished - Jan 1 2019

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Drug Interactions
Cations
Biomarkers
Kidney
Pharmaceutical Preparations
Creatinine
Macaca fascicularis
Volunteers
Healthy Volunteers
4-Quinolones
Pyrimethamine
Metabolome
Metformin
Carboxylic Acids
Glomerular Filtration Rate
Knockout Mice
Area Under Curve
Enzymes
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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Elucidation of N1-methyladenosine as a potential surrogate biomarker for drug interaction studies involving renal organic cation transporters. / Miyake, Takeshi; Mizuno, Tadahaya; Takehara, Issey; Mochizuki, Tatsuki; Kimura, Miyuki; Matsuki, Shunji; Irie, Shin; Watanabe, Nobuaki; Kato, Yukio; Ieiri, Ichiro; Maeda, Kazuya; Ando, Osamu; Kusuhara, Hiroyuki.

In: Drug Metabolism and Disposition, Vol. 47, No. 11, 01.01.2019, p. 1270-1280.

Research output: Contribution to journalArticle

Miyake, T, Mizuno, T, Takehara, I, Mochizuki, T, Kimura, M, Matsuki, S, Irie, S, Watanabe, N, Kato, Y, Ieiri, I, Maeda, K, Ando, O & Kusuhara, H 2019, 'Elucidation of N1-methyladenosine as a potential surrogate biomarker for drug interaction studies involving renal organic cation transporters', Drug Metabolism and Disposition, vol. 47, no. 11, pp. 1270-1280. https://doi.org/10.1124/dmd.119.087262
Miyake, Takeshi ; Mizuno, Tadahaya ; Takehara, Issey ; Mochizuki, Tatsuki ; Kimura, Miyuki ; Matsuki, Shunji ; Irie, Shin ; Watanabe, Nobuaki ; Kato, Yukio ; Ieiri, Ichiro ; Maeda, Kazuya ; Ando, Osamu ; Kusuhara, Hiroyuki. / Elucidation of N1-methyladenosine as a potential surrogate biomarker for drug interaction studies involving renal organic cation transporters. In: Drug Metabolism and Disposition. 2019 ; Vol. 47, No. 11. pp. 1270-1280.
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T1 - Elucidation of N1-methyladenosine as a potential surrogate biomarker for drug interaction studies involving renal organic cation transporters

AU - Miyake, Takeshi

AU - Mizuno, Tadahaya

AU - Takehara, Issey

AU - Mochizuki, Tatsuki

AU - Kimura, Miyuki

AU - Matsuki, Shunji

AU - Irie, Shin

AU - Watanabe, Nobuaki

AU - Kato, Yukio

AU - Ieiri, Ichiro

AU - Maeda, Kazuya

AU - Ando, Osamu

AU - Kusuhara, Hiroyuki

PY - 2019/1/1

Y1 - 2019/1/1

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 organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 6 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 6 2.6 and 24.3 6 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2- fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid 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 ofm1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 658 and 1696 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger 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. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasmam1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.

AB - 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 organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 6 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 6 2.6 and 24.3 6 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2- fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid 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 ofm1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 658 and 1696 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger 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. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasmam1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.

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