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

Anesth Analg. 2009 Jan;108(1):149-59. doi: 10.1213/ane.0b013e31818e0bd1.


Background: Drug transport proteins may be instrumental in controlling the concentration of fentanyl at mu 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 (P(B)) and lung:plasma (P(L)) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / pharmacokinetics
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Binding, Competitive
  • Brain / drug effects*
  • Brain / metabolism
  • Electroencephalography
  • Fentanyl / administration & dosage
  • Fentanyl / blood
  • Fentanyl / pharmacokinetics
  • Fentanyl / pharmacology*
  • Infusions, Intravenous
  • Loperamide / administration & dosage
  • Loperamide / blood
  • Loperamide / pharmacokinetics
  • Loperamide / pharmacology*
  • Lung / metabolism
  • Male
  • Models, Biological
  • Naloxone / pharmacology
  • Organic Anion Transporters / metabolism*
  • Pravastatin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Verapamil / pharmacokinetics
  • Verapamil / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B
  • Analgesics, Opioid
  • Organic Anion Transporters
  • Naloxone
  • Loperamide
  • Verapamil
  • Pravastatin
  • Fentanyl