Abstract
There is wide variation in how patients respond to therapeutics. Factors that contribute to pharmacokinetic variations include disease, genetics, drugs, age, and diet. The purpose of this study was to determine the effect of calorie restriction on the expression of Abcb1a in the intestine and whether calorie restriction can alter the absorption of an Abcb1a substrate (i.e., digoxin) in mice. Ten-week-old C57BL/6 mice were given either an ad libitum diet or a 25% calorie-restricted diet for 3 weeks. To determine digoxin absorption, mice were administered [3H]-labeled digoxin by oral gavage. Blood and intestine with contents were collected at 1, 2, 4, and 12 hours after digoxin administration. Concentrations of [3H]-digoxin in plasma and tissues were determined by liquid scintillation. Calorie restriction decreased plasma digoxin concentrations (about 60%) at 1, 2, and 4 hours after administration. Additionally, digoxin concentrations in the small intestine of calorie-restricted mice were elevated at 4 and 12 hours after administration. Furthermore, calorie restriction increased Abcb1a transcripts in the duodenum (4.5-fold) and jejunum (12.5-fold). To confirm a role of Abcb1a in the altered digoxin pharmacokinetics induced by calorie restriction, the experiment was repeated in Abcb1a/b-null mice 4 hours after drug administration. No difference in intestine or plasma digoxin concentrations were observed between ad libitum–fed and calorie-restricted Abcb1a/b-null mice. Thus, these findings support the hypothesis that calorie restriction increases intestinal Abcb1a expression, leading to decreased absorption of digoxin in mice. Because Abcb1a transports a wide variety of therapeutics, these results may be of important clinical significance.
Footnotes
- Received April 7, 2015.
- Accepted January 6, 2016.
↵1 Current affiliation (C.D.K.): Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
↵2 Current affiliation (I.L.C.): Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Hospital & Clinics, Kansas City, Missouri.
This work was supported by the National Institutes of Health [Grants ES09649 & ES025708].
These studies were presented as a lecture at the 54th Annual Meeting of the Society of Toxicology; 2015 Mar 23; San Diego, CA. The abstract was published in Toxicol Sci, 144, S1:12, 2015 (I.L.C., H.J.R., C.D.K.).
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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