Figure 4: Impact of multiple transporters and metabolizing enzymes on intracellular bioavailability (F_ic).

(a) Schematic representation of hepatocyte cultures used in this study: freshly isolated human hepatocytes in suspension show higher activity of drug-transporting proteins and metabolizing enzymes than hepatocytes cultured for 24 h in monolayer format. (b) Comparison between F_ic in suspension hepatocytes and hepatocytes cultured in monolayer format. Negatively charged compounds at pH 7.4 are represented as triangles, neutral and zwitterionic species are represented by circles, and positively charged compounds are represented by squares. Compound numbers indicate: 1) astemizole; 2) indomethacin; 3) ketoconazole; 4) atorvastatin acid; 5) propranolol; 6) ritonavir. (c) Differences in metabolic clearance in suspension hepatocytes and hepatocytes cultured in monolayer format. *p < 0.05 in Mann-Whitney test comparing suspension and monolayer hepatocytes.