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The effect of pancreatic and biliary depletion on in vivo pharmacokinetics of digoxin in pigs

Tannergren, Christer; Evilevitch, Lena LU ; Pierzynowski, Stefan LU ; Piedra, Jose Valuerde; Weström, Björn LU ; Erlwanger, Kennedy; Tatara, Marcin and Lennernas, Hans (2006) 3rd World Conference on Drug Absorption, Transport and Delivery 29(3-4). p.198-204
Abstract
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 mu g/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 adminstered intraduodenally with intact enterohepatic circulation (Control) and during... (More)
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 mu g/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 adminstered 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 +/- 10.11 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. (c) 2006 Elsevier B.V. All rights reserved. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Chapter in Book/Report/Conference proceeding
publication status
published
subject
keywords
bioavailability, cholestasis, pharmacokinetics, digoxin, beta-glycoprotein, pigs, OATP
host publication
Advances in Understanding Oral Absorption and Delivery of Problem Compounds - Selected Papers from the 3rd World Conference on Drug Absorption, Transport and Delivery (European Journal of Pharmaceutical Sciences)
volume
29
issue
3-4
pages
198 - 204
publisher
Elsevier
conference name
3rd World Conference on Drug Absorption, Transport and Delivery
external identifiers
  • wos:000242226500004
  • scopus:33750147512
ISSN
1879-0720
0928-0987
DOI
10.1016/j.ejps.2006.06.009
language
English
LU publication?
yes
id
87148406-0d7a-46fa-bfbe-907290e0d410 (old id 376609)
date added to LUP
2007-10-20 09:37:35
date last changed
2019-08-14 01:51:00
@inproceedings{87148406-0d7a-46fa-bfbe-907290e0d410,
  abstract     = {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 mu g/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 adminstered 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 &lt; 0.05). The biliary clearance decreased significantly, from 0.22 +/- 10.11 l/h/kg (Control) to 0.04 +/- 0.03 l/h/kg during pancreatic and biliary depletion (P &lt; 0.05). There was a significant decrease in elimination half-life (P &lt; 0.05) and volume of distribution (P &lt; 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. (c) 2006 Elsevier B.V. All rights reserved.},
  author       = {Tannergren, Christer and Evilevitch, Lena and Pierzynowski, Stefan and Piedra, Jose Valuerde and Weström, Björn and Erlwanger, Kennedy and Tatara, Marcin and Lennernas, Hans},
  issn         = {1879-0720},
  keyword      = {bioavailability,cholestasis,pharmacokinetics,digoxin,beta-glycoprotein,pigs,OATP},
  language     = {eng},
  number       = {3-4},
  pages        = {198--204},
  publisher    = {Elsevier},
  title        = {The effect of pancreatic and biliary depletion on in vivo pharmacokinetics of digoxin in pigs},
  url          = {http://dx.doi.org/10.1016/j.ejps.2006.06.009},
  volume       = {29},
  year         = {2006},
}