2. Academic Validation
  3. The Effects of Pregnenolone 16α-Carbonitrile Dosing on Digoxin Pharmacokinetics and Intestinal Absorption in the Rat

The Effects of Pregnenolone 16α-Carbonitrile Dosing on Digoxin Pharmacokinetics and Intestinal Absorption in the Rat

  • Pharmaceutics. 2010 Mar 15;2(1):61-77. doi: 10.3390/pharmaceutics2010061.
Simon Lowes 1 2,  Iain S Haslam 3,  Britt-Marie Fihn 4,  Constanze Hilgendorf 5,  Johan E Karlsson 6,  Nicholas L Simmons 7,  Anna-Lena Ungell 8
Affiliations

Affiliations

  • 1 Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK. simon.lowes@doctors.org.uk.
  • 2 Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. simon.lowes@doctors.org.uk.
  • 3 Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK. iain.haslam@astrazeneca.com.
  • 4 Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. britt-marie.fihn@astrazeneca.com.
  • 5 Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. constanze.hilgendorf@astrazeneca.com.
  • 6 Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. johan.e.karlsson@astrazeneca.com.
  • 7 Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK. n.l.simmons@ncl.ac.uk.
  • 8 Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden. anna-lena.ungell@astrazeneca.com.
PMID: 27721343 DOI: 10.3390/pharmaceutics2010061
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.

Keywords

ABCB1; ATP-binding cassette; P-glycoprotein; digoxin; disposition; induction; intestinal transport; pharmacokinetics; pregnane X receptor; pregnenolone 16α-carbonitrile.

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