Competitive substrates for P-glycoprotein and organic anion protein transporters differentially reduce blood organ transport of fentanyl and loperamide: Pharmacokinetics and pharmacodynamics in Sprague-Dawley rats

Abstract

BACKGROUND:: Drug transport proteins may be instrumental in controlling the concentration of fentanyl at μ receptors in the brain and may provide potential therapeutic targets for controlling an individual response to opioid administration. P-glycoprotein (P-gp) efflux transporter and organic anion transport protein inward transporters (OATP, human; Oatp, rat) have been implicated in fentanyl and verapamil (only P-gp) transport across the blood-brain barrier. We hypothesized that transport proteins P-gp and Oatp mediate opioid uptake in a drug and organ-specific manner, making them excellent potential targets for therapeutic intervention. METHODS:: Opioid (fentanyl or loperamide) was administered by IV infusion to Sprague-Dawley rats alone or in combination with competitive substrates of P-gp (verapamil) or Oatp (pravastatin, naloxone). Plasma, lung, and brain were collected over 10 min and at 60 min after opioid infusion and opioid concentration determined using liquid chromatography/mass spectrometry (LC/LC-MS/MS). Continuous electroencephalogram was used to determine the in vivo response to fentanyl and loperamide in the presence and absence of verapamil. RESULTS:: Loperamide brain:plasma (PB) and lung:plasma (PL) partitioning was increased two and fivefold, respectively in the presence of verapamil. Verapamil administration was lethal unless the loperamide dose was reduced by half (0.95-0.475 mg/kg). Fentanyl brain:plasma and lung:plasma were reduced four and sixfold, respectively, by pravastatin and naloxone, whereas verapamil had much less effect. Electroencephalogram results indicated that verapamil reduced the fentanyl-induced central nervous system (CNS) effect and increased the loperamide CNS effect. CONCLUSION:: Protein transporters appear to be organ and drug-specific in vivo, affecting first-pass pulmonary uptake and CNS response to opioid administration. Further, data suggest that transport protein inhibition may prove useful for normalizing an individual response to opioids. Copyright © 2008 International Anesthesia Research Society.