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Pharmacology

Roles of P-Glycoprotein, Bcrp, and Mrp2 in Biliary Excretion of Spiramycin in Mice

Xianbin Tian, Jun Li, Maciej J. Zamek-Gliszczynski, Arlene S. Bridges, Peijin Zhang, Nita J. Patel, Thomas J. Raub, Gary M. Pollack, Kim L. R. Brouwer
Xianbin Tian
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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Jun Li
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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Maciej J. Zamek-Gliszczynski
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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Arlene S. Bridges
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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Peijin Zhang
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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Nita J. Patel
2Eli Lilly and Company, Drug Disposition, Indianapolis, Indiana
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Thomas J. Raub
2Eli Lilly and Company, Drug Disposition, Indianapolis, Indiana
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Gary M. Pollack
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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Kim L. R. Brouwer
1School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
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  • For correspondence: kbrouwer@unc.edu
DOI: 10.1128/AAC.00082-07
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  • FIG. 1.
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    FIG. 1.

    Model scheme depicting spiramycin disposition in the single-pass perfused liver. Q, flow rate; Cin, concentration of spiramycin in inflow perfusate; Cout, concentration of spiramycin in outflow perfusate; CLup, uptake clearance into the liver; Kps, first-order rate constant for basolateral excretion; XL1, XL2, and XL3, amount of spiramycin in liver compartments 1, 2, and 3, respectively; K12 and K21, first-order rate constants for distribution between liver compartments 1 and 2, respectively; K13 and K31, first-order rate constants for distribution between liver compartments 1 and 3, respectively; Kb, first-order rate constant for biliary excretion; Xbile, amount of spiramycin in bile.

  • FIG. 2.
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    FIG. 2.

    Representative fit of the compartmental model (Fig. 1) to spiramycin outflow perfusate rate (○, ng/min) and biliary excretion rate (•, ng/min/g liver) data.

  • FIG. 3.
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    FIG. 3.

    Cumulative biliary excretion of spiramycin in mice (▵, B6; ▴, B6+GW918; ○, Mrp2KO; •, Mrp2KO+GW918; □, BcrpKO; ▪, BcrpKO+GW918). Symbols represent means ± the SD (n = three animals per group). Lines represent the simulation of cumulative biliary excretion of spiramycin (in nanograms) with the compartmental model (Fig. 1) and mean parameter estimates (Table 1).

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  • TABLE 1.

    Spiramycin recovery in perfusate and bile and pharmacokinetic parameter estimates governing spiramycin disposition in single-pass perfused livers from B6, Mrp2KO, and BcrpKO micea

    ParameterB6Mrp2KOBcrpKO
    Spiramycin recovery (% of liver content at end of infusion)
        Perfusate
            Vehicle32.5 ± 4.829.5 ± 6.028.1 ± 5.6
            GW91834.1 ± 4.524.0 ± 4.825.2 ± 2.3
        Bileb,c
            Vehicle9.15 ± 4.151.21 ± 1.2314.1 ± 2.0
            GW9184.36 ± 0.480.58 ± 0.268.28 ± 0.80
    Pharmacokinetic parameter estimates
        CLup (ml/min)
            Vehicle4.63 ± 0.375.15 ± 0.234.55 ± 0.44
            GW9184.64 ± 0.204.70 ± 0.145.03 ± 0.05
        Kps (min−1)c
            Vehicle0.488 ± 0.1780.420 ± 0.0790.453 ± 0.047
            GW9180.317 ± 0.0410.373 ± 0.0340.311 ± 0.014
        K12 (min−1)
            Vehicle0.0427 ± 0.01510.0501 ± 0.03170.0441 ± 0.0200
            GW9180.0240 ± 0.01100.0410 ± 0.00800.0209 ± 0.0040
        K21 (min−1)
            Vehicle0.1021 ± 0.03800.1434 ± 0.12610.1261 ± 0.0431
            GW9180.1012 ± 0.04070.0679 ± 0.02400.0933 ± 0.0100
        Kb(min−1)b,c
            Vehicle0.0124 ± 0.00960.0013 ± 0.00090.0270 ± 0.0153
            GW9180.0106 ± 0.00110.0004 ± 0.00010.0183 ± 0.0054
        K13 (min−1)
            Vehicle0.1066 ± 0.06180.2064 ± 0.08940.1669 ± 0.0781
            GW9180.1457 ± 0.02530.2123 ± 0.06740.2021 ± 0.0113
        K31 (min−1)
            Vehicle0.0009 ± 0.0001<0.00010.0022 ± 0.0013
            GW9180.0007 ± 0.0012<0.00010.0007 ± 0.0002
    • ↵ a Values are mean ± SD (n = 3 per group).

    • ↵ b P < 0.05, among mouse groups.

    • ↵ c P < 0.05, GW918 vs vehicle.

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Roles of P-Glycoprotein, Bcrp, and Mrp2 in Biliary Excretion of Spiramycin in Mice
Xianbin Tian, Jun Li, Maciej J. Zamek-Gliszczynski, Arlene S. Bridges, Peijin Zhang, Nita J. Patel, Thomas J. Raub, Gary M. Pollack, Kim L. R. Brouwer
Antimicrobial Agents and Chemotherapy Aug 2007, 51 (9) 3230-3234; DOI: 10.1128/AAC.00082-07

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Roles of P-Glycoprotein, Bcrp, and Mrp2 in Biliary Excretion of Spiramycin in Mice
Xianbin Tian, Jun Li, Maciej J. Zamek-Gliszczynski, Arlene S. Bridges, Peijin Zhang, Nita J. Patel, Thomas J. Raub, Gary M. Pollack, Kim L. R. Brouwer
Antimicrobial Agents and Chemotherapy Aug 2007, 51 (9) 3230-3234; DOI: 10.1128/AAC.00082-07
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KEYWORDS

ATP Binding Cassette Transporter, Subfamily B
ATP-Binding Cassette Transporters
Bile
Coccidiostats
Membrane Transport Proteins
Multidrug Resistance-Associated Proteins
Spiramycin

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