Hepatic first pass, clearance and biliary excretion of rosuvastatin and digoxin affected by cirrhosis
To study the application of NMP to assess hepatic first pass, clearance and biliary excretion, a drug cocktail (rosuvastatin, digoxin, furosemide and metformin) was infused to the portal vein (schematic presentation of experimental set-up is shown in Figure 4). The drug cocktail is representative for different important hepatic uptake and efflux transporters (Supplemental table 1; e.g. organic anion transporter protein 1B1/1B3 (OATP1B1/1B3), P-glycoprotein (Pgp), organic cation transporter 1 (OCT1), breast cancer resistance protein (BCRP). Perfusate concentrations of rosuvastatin appeared to be the most affected by liver cirrhosis, with an approximate 34-fold increased Cmax in cirrhotic livers compared to the perfused non-cirrhotic livers (463.3 ng/mL (IQR: 243.2-555.2) vs 13.50 ng/mL (IQR: 7.01-71.02), p=0.024) and 20-fold increased AUC0-tau (20962 (IQR: 11617-29981) versus 107 ng/mL (IQR:100-5154, p<0.001) (Figure 5A). A comparable effect was observed for digoxin, with a perfusate Cmax that was more than 3-fold higher in cirrhotic livers (10.03 ng/mL (IQR:7.75-11.78)) compared to non-cirrhotic livers (3.46 ng/mL ng/mL (IQR:2.33-7.80, p=0.038)) and an AUC0-tau that was almost 3-fold higher (629 ng/mL (IQR:282-746) in cirrhotic livers versus 222 ng/mL (IQR:171-503) in non-cirrhotic livers, p=0.003) (Figure 5B). Biliary excretion of rosuvastatin and digoxin was higher in cirrhotic livers (66% and 51% respectively) compared to non-cirrhotic livers (47% and 17%, respectively), however not significant (Figure 5E-F). As can be observed in Figure 5C-D, cirrhosis had a minor effect on furosemide and metformin concentrations as Cmax was 1.19 and 1.13 times higher in cirrhotic livers compared to non-cirrhotic livers (not significant). Metformin and furosemide were only minimally cleared through biliary excretion (in the range of 1-3%) which was not affected by the cirrhosis (Figure 5G-H)). The hepatic extraction was determined by sampling from the portal vein and hepatic artery. Hepatic extraction ratio of rosuvastatin tended to be affected by cirrhosis (not significant) and was 0.48 (IQR:0.42-0.67) versus 0.70 (IQR:0.69-0.83) in non-cirrhotic livers (Figure 5I). Hepatic extraction of the other drugs was not affected by cirrhosis.