Article Figures & Data
Figures
- 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.
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.
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).
Tables
- 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
Parameter B6 Mrp2KO BcrpKO Spiramycin recovery (% of liver content at end of infusion) Perfusate Vehicle 32.5 ± 4.8 29.5 ± 6.0 28.1 ± 5.6 GW918 34.1 ± 4.5 24.0 ± 4.8 25.2 ± 2.3 Bileb,c Vehicle 9.15 ± 4.15 1.21 ± 1.23 14.1 ± 2.0 GW918 4.36 ± 0.48 0.58 ± 0.26 8.28 ± 0.80 Pharmacokinetic parameter estimates CLup (ml/min) Vehicle 4.63 ± 0.37 5.15 ± 0.23 4.55 ± 0.44 GW918 4.64 ± 0.20 4.70 ± 0.14 5.03 ± 0.05 Kps (min−1)c Vehicle 0.488 ± 0.178 0.420 ± 0.079 0.453 ± 0.047 GW918 0.317 ± 0.041 0.373 ± 0.034 0.311 ± 0.014 K12 (min−1) Vehicle 0.0427 ± 0.0151 0.0501 ± 0.0317 0.0441 ± 0.0200 GW918 0.0240 ± 0.0110 0.0410 ± 0.0080 0.0209 ± 0.0040 K21 (min−1) Vehicle 0.1021 ± 0.0380 0.1434 ± 0.1261 0.1261 ± 0.0431 GW918 0.1012 ± 0.0407 0.0679 ± 0.0240 0.0933 ± 0.0100 Kb(min−1)b,c Vehicle 0.0124 ± 0.0096 0.0013 ± 0.0009 0.0270 ± 0.0153 GW918 0.0106 ± 0.0011 0.0004 ± 0.0001 0.0183 ± 0.0054 K13 (min−1) Vehicle 0.1066 ± 0.0618 0.2064 ± 0.0894 0.1669 ± 0.0781 GW918 0.1457 ± 0.0253 0.2123 ± 0.0674 0.2021 ± 0.0113 K31 (min−1) Vehicle 0.0009 ± 0.0001 <0.0001 0.0022 ± 0.0013 GW918 0.0007 ± 0.0012 <0.0001 0.0007 ± 0.0002
