The effect of pancreatic and biliary depletion on the in vivo pharmacokinetics of digoxin in pigs.
Several transporter systems in the liver and intestine are known to change their expression and function during cholestatic disease states. The objective of the present in vivo study was to investigate the effect of biliary depletion, as a method to mimic cholestasis, on the bioavailability and disposition of digoxin in biliary and pancreatic duct cannulated pigs. The study was divided in two parts. In the first part, a solution of 10 microg/kg digoxin was administered intravenously to the cannulated pigs with intact enterohepatic circulation (Control) and during depletion of the bile and pancreatic juice. In the second part, the same dose of digoxin was administered intraduodenally with intact enterohepatic circulation (Control) and during depletion of either bile or pancreatic juice or both. Biliary depletion decreased the flow of bile and pancreas juice as well as the amount of digoxin appearing in the bile. Deprivation of both bile and pancreas juice significantly increased the bioavailability of digoxin, the plasma AUC after enteral administration increased from 17.6+/-4.2 nmol/lh (Control) to 29.6+/-8.3 nmol/lh (P<0.05). The biliary clearance decreased significantly, from 0.22+/-0.11 l/h/kg (Control) to 0.04+/-0.03 l/h/kg during pancreatic and biliary depletion (P<0.05). There was a significant decrease in elimination half-life (P<0.05) and volume of distribution (P<0.01) during the depletion experiments while the systemic clearance remained unchanged. The results clearly suggest that biliary depletion trigger a short-term downregulation, most likely posttranscriptionally mediated, of a sinusoidal uptake transporter in the liver, possibly a pig ortholog of OATP.
Tannergren
Christer
C
Early Development, AstraZeneca, R&D Mölndal, Mölndal, Sweden.
Evilevitch
Lena
L
Pierzynowski
Stefan
S
Piedra
Jose Valverde
JV
Weström
Björn
B
Erlwanger
Kennedy
K
Tatara
Marcin
M
Lennernäs
Hans
H
D000818:Animals; D001682:Biological Availability; D002779:Cholestasis / Q000378:metabolism*; D004077:Digoxin / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000502:physiology; D013552:Swine
D027361:Organic Anion Transporters; D004077:Digoxin