Chronic voluntary exercise may alter hepatobiliary clearance of endogenous and exogenous chemicals in rats

J. B. Watkins, S. T. Crawford, R. A. Sanders

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21 Scopus citations

Abstract

A chronic voluntary exercise paradigm, which mimics the exercise pattern of many humans, influences the hepatic clearance of several organic anions and a bile acid, whereas a neutral organic compound is seemingly unaffected. To extend these observations, the present work has evaluated in female Sprague-Dawley rats the effect of 6 weeks of voluntary running on the hepatobiliary elimination of endogenous bile acids and glutathione and exogenously injected rose bengal, digoxin, and acetaminophen. Inactive rats had mobility limited to their cages, whereas exercised rats had free access to a 44- in running wheel. In comparison to weight-matched sedentary rats, the exercised rats ran 4.3 ± 0.3 miles/day, consumed 45% more food daily, had slightly greater liver/body weight ratios, and slightly elevated basal bile flow rates. Biliary excretion of endogenous bile acids was increased significantly, and excretion of reduced and oxidized glutathione was increased in exercised rats by 190% and 173% of sedentary levels, respectively. Total clearance, biliary clearance, and maximal biliary excretion of the injected organic anion rose bengal (60 μmol/kg) were elevated in exercised rats by 86%, 440%, and 85%, respectively. In contrast, there were no observed differences in pharmacokinetic parameters, serum elimination, or biliary excretion for the clinically important cardiac glycoside digoxin (dose of 100 nmol/kg). Finally, study of the analgesic acetaminophen (330 μmol/kg) revealed that total and biliary clearances were increased by 37% and 42%, respectively, in exercised rats, whereas steady- state volume of distribution and elimination half-life were not significantly different. HPLC analysis indicated that there was an increase in elimination of the sulfate conjugates of acetaminophen for the first hour, with an increased excretion of the glucuronide in the first 15 min. Moreover, cytosolic 2-naphthol sulfotransferase activity in liver from exercised rats was 115% greater than that in livers from sedentary rats. Kinetic analysis indicated that the K(M) for adenosine 3'-phosphate 5'-phosphosulfate was decreased by 44% in exercised rats. Thus, chronic voluntary physical activity can potentially alter the efficacy and pharmacokinetics of therapeutic agents.

Original languageEnglish (US)
Pages (from-to)537-543
Number of pages7
JournalDrug Metabolism and Disposition
Volume22
Issue number4
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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