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• Lowes, S
• Haslam, I
• Fihn, B
• Hilgendorf, C
• Karlsson, J
• Simmons, N
• Ungell, A
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• Haslam, I
• Fihn, B
• Hilgendorf, C
• Karlsson, J
• Simmons, N
• Ungell, A
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• Haslam, I
• Fihn, B
• Hilgendorf, C
• Karlsson, J
• Simmons, N
• Ungell, A

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Pharmaceutics 2010, 2(1), 61-77; doi:10.3390/pharmaceutics2010061

Article

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

Simon Lowes ^1,2 , Iain S. Haslam ^1, , Britt-Marie Fihn ² , Constanze Hilgendorf ^2,* , Johan E. Karlsson ² , Nicholas L. Simmons ¹  and Anna-Lena Ungell ²

¹ Epithelial Research Group, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, NE2 4HH, UK ² Discovery Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, 431 83 Mölndal, Sweden Current address: Drug Metabolism and Pharmacokinetics, AstraZeneca Research & Development, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.

* Author to whom correspondence should be addressed.

Received: 1 February 2010; in revised form: 5 March 2010 / Accepted: 11 March 2010 / Published: 15 March 2010

(This article belongs to the Special Issue What's on Board in Pharmaceutics)

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

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