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Research ArticleArticle

Active Transport of Fentanyl by the Blood-Brain Barrier

Thomas K. Henthorn, Yang Liu, Mrinal Mahapatro and Ka-yun Ng
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 1084-1089;
Thomas K. Henthorn
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Yang Liu
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Mrinal Mahapatro
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Ka-yun Ng
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Abstract

Previous studies have shown that uptake of the lipophilic opioid, fentanyl, by pulmonary endothelial cells occurs by both passive diffusion and carrier-mediated processes. To evaluate if the latter mechanism also exists in brain endothelium, transport of [3H]fentanyl was examined in primary cultured bovine brain microvessel endothelial cell (BBMEC) monolayers. Uptake of fentanyl appears to occur via a carrier-mediated process as uptake of [3H]fentanyl by BBMECs was significantly inhibited in a dose-dependent manner by unlabeled fentanyl. Fentanyl uptake was also significantly inhibited by either 4°C or sodium azide/2-deoxyglucose, suggesting that carrier-mediated uptake of fentanyl was an active process. Fentanyl was also tested to determine whether it might be a substrate of the endogenous blood-brain barrier efflux transport system, P-glycoprotein (P-gp). Release of [3H]fentanyl or rhodamine 123, a known substrate of P-gp, previously loaded in the BBMECs was studied in the presence or absence of either fentanyl or verapamil, a known competitive inhibitor of P-gp. Both fentanyl (10 μM) and verapamil (100 μM) decreased release of rhodamine 123 from BBMECs, indicating that fentanyl is a substrate of P-gp in the BBMECs. This was further supported by the observation that uptake of [3H]fentanyl was significantly increased in Mg2+-free medium, a condition known to reduce P-gp activity. However, release of [3H]fentanyl was significantly increased when incubated with either unlabeled fentanyl or verapamil. These results suggest that the active P-gp-mediated extrusion of fentanyl in these cells is overshadowed by an active inward transport process, mediated by an as yet unidentified transporter. In addition, verapamil was shown to be a substrate of both P-gp and the fentanyl uptake transporter.

Footnotes

  • Send reprint requests to: Dr. Thomas K. Henthorn, M.D., Department of Anesthesiology, University of Colorado Health Sciences Center, Campus Box B113 4200 E. 9th Ave., Denver, CO 80262. E-mail:tkhenthorn{at}ski.uhcolorado.edu

  • ↵1 This study was supported in part by National Institutes of Health Grant GM47502 and was presented in part at the 1998 Annual Meeting of the American Society of Anesthesiologists (Henthorn TK, Liu Y and Ng KY (1998) Evidence for a fentanyl transporter at the blood-brain barrier. Anesthesiology 89:A522).

  • Abbreviations:
    ABC
    ATP-binding cassette
    BBB
    blood-brain barrier
    BBMEC
    bovine brain microvascular endothelial cell
    BPAEC
    bovine pulmonary artery endothelial cell
    ECGS
    endothelial cell growth supplements
    EBSS
    Earl’s balanced salt solution
    KEQ equilibrium partition coefficient
    ko, rate constant of drug dissociation from transporter
    kt
    rate constant of drug association to transporter
    KM
    drug concentration which leads to 50% occupancy of transporters
    P-gp
    P-glycoprotein
    R123
    rhodamine 123
    • Received August 6, 1998.
    • Accepted December 21, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

Active Transport of Fentanyl by the Blood-Brain Barrier

Thomas K. Henthorn, Yang Liu, Mrinal Mahapatro and Ka-yun Ng
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1084-1089;

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Research ArticleArticle

Active Transport of Fentanyl by the Blood-Brain Barrier

Thomas K. Henthorn, Yang Liu, Mrinal Mahapatro and Ka-yun Ng
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 1084-1089;
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