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ANESTHETIC PHARMACOLOGY

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

Iman A. Elkiweri, MS^*, Yan Ling Zhang, PhD, Uwe Christians, MD, PhD, Ka-Yun Ng, PhD, Martha C. Tissot van Patot, PhD, and Thomas K. Henthorn, MD

From the *College of Nursing, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado; Department of Anesthesiology, University of Colorado Denver Health Sciences Center, Denver, Colorado; and Department of Pharmacy, National University of Singapore, Singapore.

Address correspondence and reprint requests to Martha Tissot van Patot, PhD, Department of Anesthesiology, Campus Box 8202, Bldg. AO1, Room L15-2009, University of Colorado at Denver and Health Sciences Center, PO Box 6511, 12631 E. 17th Ave., Aurora, CO 80045. Address e-mail to martha.tissotvanpatot{at}ucdenver.edu.

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 (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.