TABLE 6

The effects of zonal heterogeneity of influx/efflux transport, metabolism, and secretion on clearances in digoxin hepatic disposition: simulations with the PBPK zonal model (Fig. 4B) The three letters denote the distribution patterns of influx/efflux, metabolism, and secretory activities, with A denoting even distribution, B denoting 10:30:60% of total activity, and C denoting 60:30:10% of total activity in zones 1, 2, and 3, respectively.



Control Condition (CLin = 12.1 ml/min/g; CLef = 14.1 ml/min/g; CLint,met = 0.197 ml/min/g; CLint,sec = 0.017 ml/min/g)

Assigned Metabolic or Secretory Intrinsic Clearances

5× CLint,met; 50× CLint,sec
100× CLint,met; 500× CLint,sec
0.1× CLint,sec
Best condition
   CLliver,tot (ml/min/g) 0.11378 (AAA) 0.5064 (AAA) 0.7653 (AAA) 0.10620 (AAC)
0.11377 (AAC) 0.5061 (ACB) 0.7649 (AAC) 0.10620 (AAA)
0.11377 (AAB) 0.5061 (ABC) 0.7649 (AAB) 0.10620 (AAB)
   CLliver,met (ml/min/g) 0.10480 (AAB) 0.3118 (CCB) 0.6592 (CCB) 0.10530 (AAB)
0.10458 (AAA) 0.3085 (ACB) 0.6424 (ACB) 0.10527 (AAA)
0.10436 (AAC) 0.2947 (AAB) 0.6308 (CAB) 0.10525 (AAC)
   CLliver,ex (ml/min/g) 0.00977 (ABC) 0.2826 (CBC) 0.4642 (CBC) 0.00098 (ABC)
0.00973 (CBC) 0.2798 (ABC) 0.4419 (ABC) 0.00098 (CBC)
0.00969 (BBC) 0.2632 (ABA) 0.3845 (CBA) 0.00098 (BBC)
Worst condition
   CLliver,tot (ml/min/g) 0.10867 (CBB) 0.4427 (CBB) 0.7356 (BCC) 0.10170 (CBB)
0.10868 (BCC) 0.4427 (BCC) 0.7356 (CBB) 0.10171 (BCC)
0.10916 (CBA) 0.4719 (CBA) 0.7464 (BCA) 0.10175 (CBA)
   CLliver,met (ml/min/g) 0.09986 (CBC) 0.2064 (CBC) 0.2878 (CBC) 0.10081 (CBC)
0.09987 (CBA) 0.2167 (CBA) 0.3228 (ABC) 0.10081 (CBA)
0.09988 (CBB) 0.2263 (ABC) 0.3620 (CBA) 0.10081 (CBB)
   CLliver,ex (ml/min/g) 0.00879 (CBB) 0.1803 (CCB) 0.1223 (CCB) 0.00089 (CBB)
0.00879 (BCC) 0.1891 (CAB) 0.1220 (CAB) 0.00089 (BCC)

0.00880 (CAB)
0.1976 (ACB)
0.0978 (ACB)
0.00089 (CAB)