Fig. 4.
Simulations depicting the impact of impaired function of canalicular and/or basolateral efflux transporters on hepatic TCA exposure. Cellular TCA concentrations in human and rat SCH were simulated based on the TCA model scheme depicted in Fig. 1 and parameter estimates (Table 1) for human SCH (A), rat SCH (B), and rat SCH where CLUptake was 5× the value listed in Table 1 (C). Parameters representing transport-mediated efflux (CLBL and CLBile) were decreased by 10-fold in isolation, or in combination, to represent impaired function of canalicular efflux transporters (solid line with open circle), basolateral efflux transporters (dashed line), and both pathways (dashed line with closed circle). Simulations were performed for 200 minutes to obtain steady-state intracellular concentrations; the time to reach steady state was longer when efflux pathways were impaired compared with control (solid line).