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.