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.
authors.affiliation: Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK. simon.lowes@doctors.org.uk.|Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. simon.lowes@doctors.org.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Lowes
authors.affiliation: Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK. iain.haslam@astrazeneca.com.
authors.forename: Iain S
authors.initials: IS
authors.lastname: Haslam
authors.affiliation: Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. britt-marie.fihn@astrazeneca.com.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Fihn
authors.affiliation: Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. constanze.hilgendorf@astrazeneca.com.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilgendorf
authors.affiliation: Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. johan.e.karlsson@astrazeneca.com.
authors.forename: Johan E
authors.initials: JE
authors.lastname: Karlsson
authors.affiliation: Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK. n.l.simmons@ncl.ac.uk.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Simmons
authors.affiliation: Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. anna-lena.ungell@astrazeneca.com.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ungell
keywords: ABCB1; ATP-binding cassette; P-glycoprotein; digoxin; disposition; induction; intestinal transport; pharmacokinetics; pregnane X receptor; pregnenolone 16α-carbonitrile