Abstract
<p><strong>Objective: </strong>Various nutrients such as glucose and cholesterol affect the expression of hepatic transporters. Although the pharmacokinetics of some drugs is affected by fasting, the fasting effects on drug hepatic disposition via alterations in transporters are unclear. Organic anion-transporting polypeptides and multidrug resistance-associated protein 2 (Mrp2/Abcc2) expressed in the liver are involved in hepatic disposition of pravastatin.</p><p><strong>Methods: </strong>An <em>in situ</em> perfused rat liver system was established. The mRNA and protein levels of transporters in the liver were examined by real-time reverse transcription PCR and western blotting. The localization of Mrp2 in hepatocytes was determined by immunostaining.</p><p><strong>Results: </strong>Pravastatin was rapidly eliminated from the perfusate. The cumulative biliary excretion amounts of pravastatin in fasting rats were significantly lower from 10 min compared with control. In fasting rats, the area under the plasma concentration-time curve (<em>AUC</em>)<sub>0‒∞</sub> of pravastatin in the perfusate was significantly decreased, and hepatic clearance (<em>CL<sub>h</sub></em>) and hepatic corrected clearance (<em>CL<sub>cor</sub></em>) were significantly increased. The biliary clearance (<em>CL<sub>bile</sub></em>) in fasting rats tended to decrease compared with that in control rats. Protein expression levels of transporters were unchanged after fasting. Confocal microscopy revealed a disruption of Mrp2 and ZO-1 colocalization in the liver of fasting rats.</p><p><strong>Conclusion: </strong>The biliary excretion of pravastatin was inhibited by fasting via decreased Mrp2 localization on the canalicular membrane.</p>
Highlights
Increases in plasma fatty acids and ketones, and a decrease in plasma glucose levels are observed upon fasting or short-term calorie restriction, and fatty acids are the main energy source during fasting [1, 2]
The plasma cholesterol levels were significantly decreased and the plasma ketone levels were significantly increased compared with the control rats
Pravastatin was rapidly eliminated from the perfusate and the perfusate concentration reached less than 10% of the dose after 10 min of perfusion
Summary
Increases in plasma fatty acids and ketones, and a decrease in plasma glucose levels are observed upon fasting or short-term calorie restriction, and fatty acids are the main energy source during fasting [1, 2]. Multidrug resistance-associated protein 2 (Mrp2/Abcc2) in ABC transporters is expressed on the apical side of hepatocytes, and transports drugs and drug metabolites such as glucuronides [12,13,14]. Various nutrients such as glucose and cholesterol affect the expression of hepatic transporters [15,16,17,18]. It is unclear whether fasting affects hepatic drug disposition via alterations in the expression of transporters
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