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Research ArticleArticle

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 and Hiroyuki Kusuhara
Drug Metabolism and Disposition November 2019, 47 (11) 1270-1280; DOI: https://doi.org/10.1124/dmd.119.087262
Takeshi Miyake
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Tadahaya Mizuno
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Issey Takehara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Tatsuki Mochizuki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Miyuki Kimura
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Shunji Matsuki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Shin Irie
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Nobuaki Watanabe
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Yukio Kato
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Ichiro Ieiri
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Kazuya Maeda
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Osamu Ando
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Tak.M., Tad.M., Tat.M., K.M., H.K.); Biomarker Department (I.T.) and Drug Metabolism & Pharmacokinetics Research Laboratories (N.W., O.A.), Daiichi-Sankyo Co., Ltd., Tokyo, Japan; Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, Japan (M.K., S.M., S.I.); Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (Y.K.); and Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (I.I.)
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  • Fig. 1.
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    Fig. 1.

    In vitro transport study of m1A. The uptake of m1A (100 μM) by organic cation transporters was determined in the absence (solid lines) or presence (dotted lines) of inhibitor (5 mM TEA). The incubation buffer also contained 10 μM dipyridamole to inhibit the ENT-mediated m1A uptake. Each symbol and bar represents the mean ± S.E. (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001, the absence vs. presence of 5 mM TEA in transporter-overexpressing cells, Student’s two-tailed unpaired t test.

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    Fig. 2.

    Effect of various inhibitors on hOCT2- and hMATE2-K-mediated m1A uptake. The uptake of m1A (100 μM) for 60 minutes in HEK293 cells stably expressing hOCT2 or hMATE2-K was determined in the absence and presence of inhibitors (trimethoprim, pyrimethamine, and cimetidine) at the designated concentrations. The transporter-specific uptake of m1A was calculated by subtracting the uptake by empty vector–transfected cells from that by transporter-expressing cells and shown as a proportion to the uptake value in the absence of inhibitors. The solid line represents the fitted line obtained by nonlinear regression analysis as described in Materials and Methods. Each symbol and bar represents the mean ± S.E. (n = 3).

  • Fig. 3.
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    Fig. 3.

    m1A uptake by renal cortical slices of WT and Oct1/2 dKO mice. The uptake of m1A (100 μM) for 10 minutes in renal cortical slices of WT and Oct1/2 dKO mice was determined in the absence or presence of 250 μM probenecid or 5 mM TEA. Each bar represents the mean ± S.E. (n = 3). **P < 0.01, Dunnett’s post hoc test.

  • Fig. 4.
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    Fig. 4.

    m1A infusion assay using WT and Oct1/2 dKO mice. Effect of Oct1/2 dKO on the plasma and concentrations and urinary excretion of exogenously given m1A (100 nmol/min per kilogram) in mice. The kinetic parameters were calculated as described in Materials and Methods. Each symbol and bar represents the mean and S.E. (n = 3). *P < 0.05; **P < 0.01, Student’s two-tailed unpaired t test.

  • Fig. 5.
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    Fig. 5.

    Effect of PYR on the kinetics of m1A in mice. Plasma concentrations and urinary excretion of m1A were determined in control and PYR-treated mice. PYR (20 μmol/kg) was given to mice by bolus injection 30 minutes before starting intravenous infusion of (A) m1A (100 nmol/min per kilogram) and (B) rhodamine 123 (1 nmol/min per kilogram). The kinetic parameters were calculated as described in Materials and Methods. Each symbol and bar represents the mean and S.E. (n = 4). *P < 0.05; **P < 0.01; ***P < 0.001, Student’s two-tailed unpaired t test.

  • Fig. 6.
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    Fig. 6.

    In vivo inhibition study of OCT2 and MATEs using DX-619. Plasma concentration profiles of m1A, metformin, creatinine, and DX-619 were determined after oral administration of metformin (5 mg/kg) with (□) and without (■) DX-619 pretreatment (30 mg/kg) in cynomolgus monkeys. Each symbol and bar represents the mean and S.E. (n = 3). P value was calculated by Student’s two-tailed paired t test.

  • Fig. 7.
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    Fig. 7.

    Plasma concentrations and renal clearance of m1A in younger and older volunteers. Plasma concentration profiles and urinary excretion of m1A and creatinine (A) in younger and older volunteers (B) were determined. Each symbol and bar represents the mean ± S.D. of eight and seven subjects. *P < 0.05; **P < 0.01; ***P < 0.001, younger vs. older, Student’s two-tailed unpaired t test.

Tables

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    TABLE 1

    List of endogenous compounds of interest in the metabolomics analysis performed on WT and Oct1/2 dKO mice

    IdentityPlatformProtonated MoleculeFold Change (Oct1/2 dKO/WT)
    PlasmaUrine
    PipecolateLC-MS Pos130.11.43***1.1
    CadaverineGC-MS174N/D0.43*
    3-methylglutarylcarnitineLC-MS Pos290.12.65**1.9
    S-methylcysteineGC-MS162.11.040.54*
    PutrescineGC-MS1740.930.62**
    DocosahexaenoateLC-MS Neg327.31.35**N/D
    DihomolinolenateLC-MS Neg305.41.26*N/D
    ArachidonateLC-MS Neg303.41.28*N/D
    DocosapentaenoateLC-MS Neg329.42.23**N/D
    Mead acidLC-MS Neg305.41.51**N/D
    12,13-DiHOMELC-MS Neg313.41.69**N/D
    CholineLC-MS Pos104.21.21*N/D
    1-DocosahexaenoylglycerophosphocholineLC-MS Pos568.41.14*N/D
    1-Docosahexaenoyl-glycerophosphoethanolamineLC-MS Neg524.31.31*N/D
    N1-methyladenosineLC-MS Pos282.12.78**0.84
    3-UreidopropionateLC-MS Pos133.10.55*0.66*
    Glycolate (hydroxyacetate)GC-MS1771.23*1.19
    X-11478aLC-MS Neg165.22***N/D
    X-11909aLC-MS Neg297.31.86**N/D
    X-12257aLC-MS Neg269.13.13*0.77
    X-16570aLC-MS Neg198.22.95*1.29
    X-16575aLC-MS Neg293.12.04***N/D
    X-16581aLC-MS Pos304.12.36***2.77**
    X-17307aLC-MS Pos162.1N/D0.48**
    X-18628aLC-MS Pos931.42.16*N/D
    X-20568aLC-MS Pos188.1N/D0.56*
    • GC-MS, gas chromatography/mass spectrometry; LC-MS, liquid chromatography/mass spectrometry; Neg, negative; Pos, positive; 12, 13-DiHOME, (±)12,13-dihydroxy-9Z-octadecenoic acid. N/D, Not detected. *P < 0.05; **P < 0.01; ***P < 0.001, Welch's two-sample t test; value in Oct1/2 dKO mice vs. WT mice.

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    TABLE 2

    Comparison of in vitro inhibition constant of various drugs for OCT2- and MATE2-K–mediated uptake

    Each value was determined from the data shown in Fig. 2. The equations for the calculations are described in Materials and Methods. Each value represents the mean ± computer-calculated S.D.

    InhibitorhOCT2hMATE2-K
    m1A 100 μMCreatinine 100 μMMetformin 10 μMm1A 100 μMCreatinine 100 μMMetformin 10 μM
    Trimethoprim20 ± 526 ± 220 ± 22.4 ± 0.40.58 ± 0.110.92 ± 0.04
    Pyrimethamine0.64 ± 0.180.93 ± 0.040.61 ± 0.040.22 ± 0.060.35 ± 0.050.22 ± 0.02
    Cimetidine1.8 ± 0.436 ± 359 ± 1.45.3 ± 1.624 ± 55.2 ± 0.8
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    TABLE 3

    Pharmacokinetic parameters of m1A in WT and Oct1/2 dKO mice

    The equations to calculate the kinetic parameters are described in Materials and Methods. Each value represents the mean ± S.E. (n = 3).

    ParameterWTOct1/2 dKO
    Cp,120 min (μM)1.63 ± 0.23*2.45 ± 0.11*
    AUCp,0–120 min (µmol per min/l)138 ± 15*203 ± 9*
    Xurine (nmol)220 ± 27*103 ± 13*
    Cliver (μM)3.31 ± 0.49*5.63 ± 0.28*
    Kp,liver (ml/g of liver)2.08 ± 0.362.30 ± 0.09
    Ckidney (μM)15.6 ± 6.79.27 ± 0.91
    Kp,kidney (ml/g of kidney)8.81 ± 2.703.76 ± 0.23
    CLtot,p (ml/min)2.10 ± 0.13**1.11 ± 0.04**
    CLtot,p (ml/min per kilogram)61.1 ± 2.7**36.4 ± 1.3**
    CLr,p (ml/min)1.61 ± 0.16**0.511 ± 0.077**
    CLr,p (ml/min per kilogram)46.9 ± 4.9**16.6 ± 2.6**
    GFR (Jonker et al., 2003)0.462 ± 0.0450.462 ± 0.065
    • Ckidney, kidney concentration; Cp,120 min, plasma concentration of compound at 120 minutes after administration; GFR, glomerular filtration rate; Kp,liver, liver-to-plasma ratio; Xurine, amount of compound excreted in urine.

    • ↵* P < 0.05; **P < 0.01; ***P < 0.001, Student’s two-tailed unpaired t test; value in Oct1/2 dKO mice vs. WT mice.

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    TABLE 4

    Pharmacokinetic parameters of m1A and rhodamine 123 in control and PYR-treated mice

    The equations to calculate the kinetic parameters are described in Materials and Methods. Each value represents the mean ± S.E. (n = 4); Student’s two-tailed unpaired t test; value in control mice vs. PYR-treated mice.

    Parameterm1ARhodamine 123
    ControlPYRUnitControlPYRUnit
    Cp,120 min1.64 ± 0.102.31 ± 0.13**μM5.61 ± 0.465.01 ± 0.39nM
    AUCp,0–120 min140 ± 9182 ± 11*μmol per min/l564 ± 27512 ± 12nmol per min/l
    Xurine170 ± 10126 ± 5**nmol477 ± 3221.2 ± 3.4***pmol
    Ckidney7.22 ± 1.8234.0 ± 5.4**μM0.800 ± 0.0741.86 ± 0.21μM
    Kp,kidney4.4 ± 1.114.7 ± 2.0**ml/g of kidney143 ± 6381 ± 70ml/g of kidney
    CLtot,p2.32 ± 0.121.78 ± 0.13*ml/min3.93 ± 0.184.07 ± 0.05ml/min
    CLtot,p80.4 ± 4.961.9 ± 3.6*ml/min per kilogram136 ± 8142 ± 2ml/min per kilogram
    CLr,p1.23 ± 0.110.698 ± 0.035**ml/min0.851 ± 0.0730.0416 ± 0.0073ml/min
    CLr,p42.6 ± 4.124.3 ± 0.6**ml/min per kilogram29.6 ± 3.11.44 ± 0.21ml/min per kilogram
    GFR (Jonker et al., 2003)0.462 ± 0.0450.462 ± 0.065ml/min
    • Ckidney, kidney concentration; Cp,120 min, plasma concentration of compound at 120 minutes after administration; GFR, glomerular filtration rate; Xurine, amount of compound excreted in urine.

    • ↵* P < 0.05; **P < 0.01; ***P < 0.001.

    • View popup
    TABLE 5

    The AUCs of metformin and m1A in control and DX-619-treated monkeys

    Treatment123Mean ± S.E.
    m1A (nM·h)
     Control364216219266 ± 49
     +DX-619468361464431 ± 35
     Fold change1.291.672.121.72 ± 0.24
    Metformin (μM·h)
     Control43.511.138.331.0 ± 10.0
     +DX-61991.926.577.665.3 ± 19.9
     Fold change2.112.392.032.18 ± 0.11
    • View popup
    TABLE 6

    Pharmacokinetic parameters of m1A in younger and older Japanese volunteers

    Each value was determined from the data shown in Fig. 7. The equations to calculate the kinetic parameters are described in Materials and Methods. Each value represents the mean ± S.D. of eight and seven subjects; Student’s two-tailed unpaired t test; younger vs. older. Subject information is shown in Supplemental Table 4.

    Parameterm1ACreatinine
    YoungerOlderUnitYoungerOlderUnit
    AUC0–24 h1.22 ± 0.221.29 ± 0.14μmol per h/l1.05 ± 0.121.04 ± 0.16mmol per h/l
    Xurine, 0–24 h17.2 ± 1.413.0 ± 0.9***μmol8.06 ± 0.796.61 ± 1.17mmol
    CLr,p244 ± 58169 ± 22**ml/min129 ± 18108 ± 21ml/min
    • AUC0–24 h, area under the plasma concentration-time curve from 0 to 24 hours; Xurine, 0–24 h, amount excreted into the urine from 0 to 24 hours.

    • ↵** P < 0.01; ***P < 0.001.

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Data -

      Supplementary Materials and Methods

      Supplementary References

      Supplementary Figure 1 - The effect of dipyridamole on the m1A uptake in HEK293 cells and the function of renal cation transporters.  

      Supplementary Figure 2 - The effect of G808T mutation to the uptake of m1A by hOCT2.

      Supplementary Figure 3 - The affinity of m1A to renal cation transporters. 

      Supplementary Figure 4 - The uptake of m1A by cynomolgus monkey OCT2.

      Supplementary Figure 5 - The effect of gut flora to the systemic exposure of m1A.

      Supplementary Figure 6 - m1A infusion assay using WT and Mdr1a/1b/Abcg2 TKO mice. 

      Supplementary Table 1 - Participants' information.

      Supplementary Table 2 - Analytical conditions for test compounds in cell, mice and human biological specimens.

      Supplementary Table 3 - Analytical conditions for metformin and DX-619 in monkey plasma specimens.

      Supplementary Table 4 - Pharmacokinetic parameters of m1A between wild-type and Mdrla/1b/Abcg2 TKO mice.

      Supplementary Table 5 - OCT2 variants associated with serum m1A in GWAS study (Shin et al., 2014)


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Drug Metabolism and Disposition: 47 (11)
Drug Metabolism and Disposition
Vol. 47, Issue 11
1 Nov 2019
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Research ArticleArticle

Endogenous Probe of 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 and Hiroyuki Kusuhara
Drug Metabolism and Disposition November 1, 2019, 47 (11) 1270-1280; DOI: https://doi.org/10.1124/dmd.119.087262

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Research ArticleArticle

Endogenous Probe of 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 and Hiroyuki Kusuhara
Drug Metabolism and Disposition November 1, 2019, 47 (11) 1270-1280; DOI: https://doi.org/10.1124/dmd.119.087262
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