The Effects of pregnenolone 16α-carbonitrile dosing on digoxin pharmacokinetics and intestinal absorption in the rat

Simon Lowes; Iain S. Haslam; Britt Marie Fihn; Constanze Hilgendorf; Johan E. Karlsson; Nicholas L. Simmons; Anna Lena Ungell

doi:10.3390/pharmaceutics2010061

The Effects of pregnenolone 16α-carbonitrile dosing on digoxin pharmacokinetics and intestinal absorption in the rat

Simon Lowes, Iain S. Haslam, Britt Marie Fihn, Constanze Hilgendorf, Johan E. Karlsson, Nicholas L. Simmons, Anna Lena Ungell

Research output: Contribution to journal › Article › peer-review

Abstract

The effect of Pgp induction in rats by pregnenolone 16α-carbonitrile (PCN) (3 days, 35 mg/kg/d, p.o.) on digoxin pharmacokinetics and intestinal transport has been assessed. After intravenous or oral digoxin dosing the arterial and hepatic portal vein (oral) AUC (0-24h) were significantly reduced by PCN pre-treatment. Biliary digoxin clearance increased 2-fold following PCN treatment. PCN significantly increased net digoxin secretion (2.05- and 4.5-fold respectively) in ileum and colon but not in duodenum or jejunum. This increased secretion correlated with increased Pgp protein expression in ileum and colon. Both intestinal and biliary excretion therefore contribute to altered digoxin disposition following PCN. © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

Original language	English
Pages (from-to)	61-77
Number of pages	16
Journal	Pharmaceutics
Volume	2
Issue number	1
DOIs	https://doi.org/10.3390/pharmaceutics2010061
Publication status	Published - Mar 2010

Keywords

ABCB1
ATP-binding cassette
Digoxin
Disposition
Induction
Intestinal ransport
P-glycoprotein
Pharmacokinetics
Pregnane X receptor
Pregnenolone 16α-carbonitrile

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@article{efbbe9d2e5894a6cbd45abd7b8be18e9,

title = "The Effects of pregnenolone 16α-carbonitrile dosing on digoxin pharmacokinetics and intestinal absorption in the rat",

abstract = "The effect of Pgp induction in rats by pregnenolone 16α-carbonitrile (PCN) (3 days, 35 mg/kg/d, p.o.) on digoxin pharmacokinetics and intestinal transport has been assessed. After intravenous or oral digoxin dosing the arterial and hepatic portal vein (oral) AUC (0-24h) were significantly reduced by PCN pre-treatment. Biliary digoxin clearance increased 2-fold following PCN treatment. PCN significantly increased net digoxin secretion (2.05- and 4.5-fold respectively) in ileum and colon but not in duodenum or jejunum. This increased secretion correlated with increased Pgp protein expression in ileum and colon. Both intestinal and biliary excretion therefore contribute to altered digoxin disposition following PCN. {\textcopyright} 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.",

keywords = "ABCB1, ATP-binding cassette, Digoxin, Disposition, Induction, Intestinal ransport, P-glycoprotein, Pharmacokinetics, Pregnane X receptor, Pregnenolone 16α-carbonitrile",

author = "Simon Lowes and Haslam, {Iain S.} and Fihn, {Britt Marie} and Constanze Hilgendorf and Karlsson, {Johan E.} and Simmons, {Nicholas L.} and Ungell, {Anna Lena}",

year = "2010",

month = mar,

doi = "10.3390/pharmaceutics2010061",

language = "English",

volume = "2",

pages = "61--77",

journal = "Pharmaceutics",

publisher = "MDPI",

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T1 - The Effects of pregnenolone 16α-carbonitrile dosing on digoxin pharmacokinetics and intestinal absorption in the rat

AU - Lowes, Simon

AU - Haslam, Iain S.

AU - Fihn, Britt Marie

AU - Hilgendorf, Constanze

AU - Karlsson, Johan E.

AU - Simmons, Nicholas L.

AU - Ungell, Anna Lena

PY - 2010/3

Y1 - 2010/3

N2 - The effect of Pgp induction in rats by pregnenolone 16α-carbonitrile (PCN) (3 days, 35 mg/kg/d, p.o.) on digoxin pharmacokinetics and intestinal transport has been assessed. After intravenous or oral digoxin dosing the arterial and hepatic portal vein (oral) AUC (0-24h) were significantly reduced by PCN pre-treatment. Biliary digoxin clearance increased 2-fold following PCN treatment. PCN significantly increased net digoxin secretion (2.05- and 4.5-fold respectively) in ileum and colon but not in duodenum or jejunum. This increased secretion correlated with increased Pgp protein expression in ileum and colon. Both intestinal and biliary excretion therefore contribute to altered digoxin disposition following PCN. © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

AB - The effect of Pgp induction in rats by pregnenolone 16α-carbonitrile (PCN) (3 days, 35 mg/kg/d, p.o.) on digoxin pharmacokinetics and intestinal transport has been assessed. After intravenous or oral digoxin dosing the arterial and hepatic portal vein (oral) AUC (0-24h) were significantly reduced by PCN pre-treatment. Biliary digoxin clearance increased 2-fold following PCN treatment. PCN significantly increased net digoxin secretion (2.05- and 4.5-fold respectively) in ileum and colon but not in duodenum or jejunum. This increased secretion correlated with increased Pgp protein expression in ileum and colon. Both intestinal and biliary excretion therefore contribute to altered digoxin disposition following PCN. © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

KW - ABCB1

KW - ATP-binding cassette

KW - Digoxin

KW - Disposition

KW - Induction

KW - Intestinal ransport

KW - P-glycoprotein

KW - Pharmacokinetics

KW - Pregnane X receptor

KW - Pregnenolone 16α-carbonitrile

U2 - 10.3390/pharmaceutics2010061

DO - 10.3390/pharmaceutics2010061

M3 - Article

VL - 2

SP - 61

EP - 77

JO - Pharmaceutics

JF - Pharmaceutics

IS - 1

ER -

The Effects of pregnenolone 16α-carbonitrile dosing on digoxin pharmacokinetics and intestinal absorption in the rat

Abstract

Keywords

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