Bile salt transport across hepatocytes requires a coordinate action of transporters, which is thought to be a target for drug-induced cholestasis. Hepatocytes provide the most competent in vitro model to predict transporter-related toxic drug effects. The aim of this study was to show a correlation between inhibitory potential of drugs and the change of rate, as well as of the active to passive ratio of taurocholate uptake in these cells. In rat hepatocytes, along with a significant decrease of uptake (86.4% by 72h), and the shift of saturable/unsaturable transport (from 92/8 to 55/45 in a 24-72h time interval), the efficacy of taurocholate uptake inhibition was highly reduced (IC(50) cyclosporin A 3.9 to >100μM, and bosentan 9.1-49.8μM at 1 and 72h, respectively). In contrast, 5-day-old human hepatocytes preserved 70% of their taurocholate uptake capacity with a 2-fold higher active than passive transport, which resulted in a more efficient inhibition by drugs (IC(50) cyclosporin A, 2.4 to ∼10μM and bosentan 28.9-45.5μM at 1h and 5days, respectively). Our results support that reliable drug interaction studies might be performed in 5-day-old human hepatocyte cultures, while experiments using rat hepatocytes at more than 24h after seeding will highly underestimate the probability of drug interaction.
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