Facilitated uptake of fentanyl, but not alfentanil, by human pulmonary endothelial cells

Christopher Waters, Tom C. Krejcie, Michael J. Avram

Research output: Contribution to journalArticle

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Abstract

Background: Extensive pulmonary uptake of lipophilic basic amines, such as fentanyl, attenuates early blood drug concentrations after rapid intravenous administration. The basis of this phenomenon is poorly understood. The authors tested the hypothesis that fentanyl uptake into cultured human lung microvascular endothelial (HMVE-L) cells occurs by facilitated uptake in addition to passive diffusion. The authors compared fentanyl and alfentanil uptake with that of antipyrine, a diffusible marker of pulmonary tissue water. In addition, the authors determined the effect of verapamil, a nonspecific inhibitor of drug transport, and UIC2, a blocking antibody of the P-glycoprotein drug transporter, on the uptake of these drugs. Methods: Human lung microvascular endothelial cells were incubated, with varying concentrations of antipyrine and fentanyl or alfentanil in the absence or presence of varying verapamil concentrations or of UIC2. Supernatants were collected and cells were rinsed and dissolved. Supernatant and cell-associated antipyrine, fentanyl, and alfentanil concentrations were measured. The data were fit to a model of cellular uptake that allowed for passive diffusion and facilitated uptake. Results: Alfentanil uptake by HMVE-L cells was indistinguishable from that of antipyrine for the concentration ranges studied. In contrast, at low concentrations, fentanyl sequestration into HMWE-L cells was substantially greater than that of antipyrine. Facilitated fentanyl uptake was blocked by verapamll, but not by UIC2, in a concentration-dependent manner. Conclusions: The differential HMVE-L uptake of fentanyl and alfentanil is consistent with the observed differences in the pulmonary uptake of these drugs. This suggests that specific fentanyl uptake and sequestration by HMVE-L cells may be the mechanisms of its extensive pulmonary uptake.

Original languageEnglish (US)
Pages (from-to)825-831
Number of pages7
JournalAnesthesiology
Volume93
Issue number3
DOIs
StatePublished - Jan 1 2000

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Alfentanil
Fentanyl
Endothelial Cells
Antipyrine
Lung
Pharmaceutical Preparations
Verapamil
Facilitated Diffusion
Blocking Antibodies
P-Glycoprotein
Intravenous Administration
Amines

All Science Journal Classification (ASJC) codes

  • Anesthesiology and Pain Medicine

Cite this

Facilitated uptake of fentanyl, but not alfentanil, by human pulmonary endothelial cells. / Waters, Christopher; Krejcie, Tom C.; Avram, Michael J.

In: Anesthesiology, Vol. 93, No. 3, 01.01.2000, p. 825-831.

Research output: Contribution to journalArticle

Waters, Christopher ; Krejcie, Tom C. ; Avram, Michael J. / Facilitated uptake of fentanyl, but not alfentanil, by human pulmonary endothelial cells. In: Anesthesiology. 2000 ; Vol. 93, No. 3. pp. 825-831.
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N2 - Background: Extensive pulmonary uptake of lipophilic basic amines, such as fentanyl, attenuates early blood drug concentrations after rapid intravenous administration. The basis of this phenomenon is poorly understood. The authors tested the hypothesis that fentanyl uptake into cultured human lung microvascular endothelial (HMVE-L) cells occurs by facilitated uptake in addition to passive diffusion. The authors compared fentanyl and alfentanil uptake with that of antipyrine, a diffusible marker of pulmonary tissue water. In addition, the authors determined the effect of verapamil, a nonspecific inhibitor of drug transport, and UIC2, a blocking antibody of the P-glycoprotein drug transporter, on the uptake of these drugs. Methods: Human lung microvascular endothelial cells were incubated, with varying concentrations of antipyrine and fentanyl or alfentanil in the absence or presence of varying verapamil concentrations or of UIC2. Supernatants were collected and cells were rinsed and dissolved. Supernatant and cell-associated antipyrine, fentanyl, and alfentanil concentrations were measured. The data were fit to a model of cellular uptake that allowed for passive diffusion and facilitated uptake. Results: Alfentanil uptake by HMVE-L cells was indistinguishable from that of antipyrine for the concentration ranges studied. In contrast, at low concentrations, fentanyl sequestration into HMWE-L cells was substantially greater than that of antipyrine. Facilitated fentanyl uptake was blocked by verapamll, but not by UIC2, in a concentration-dependent manner. Conclusions: The differential HMVE-L uptake of fentanyl and alfentanil is consistent with the observed differences in the pulmonary uptake of these drugs. This suggests that specific fentanyl uptake and sequestration by HMVE-L cells may be the mechanisms of its extensive pulmonary uptake.

AB - Background: Extensive pulmonary uptake of lipophilic basic amines, such as fentanyl, attenuates early blood drug concentrations after rapid intravenous administration. The basis of this phenomenon is poorly understood. The authors tested the hypothesis that fentanyl uptake into cultured human lung microvascular endothelial (HMVE-L) cells occurs by facilitated uptake in addition to passive diffusion. The authors compared fentanyl and alfentanil uptake with that of antipyrine, a diffusible marker of pulmonary tissue water. In addition, the authors determined the effect of verapamil, a nonspecific inhibitor of drug transport, and UIC2, a blocking antibody of the P-glycoprotein drug transporter, on the uptake of these drugs. Methods: Human lung microvascular endothelial cells were incubated, with varying concentrations of antipyrine and fentanyl or alfentanil in the absence or presence of varying verapamil concentrations or of UIC2. Supernatants were collected and cells were rinsed and dissolved. Supernatant and cell-associated antipyrine, fentanyl, and alfentanil concentrations were measured. The data were fit to a model of cellular uptake that allowed for passive diffusion and facilitated uptake. Results: Alfentanil uptake by HMVE-L cells was indistinguishable from that of antipyrine for the concentration ranges studied. In contrast, at low concentrations, fentanyl sequestration into HMWE-L cells was substantially greater than that of antipyrine. Facilitated fentanyl uptake was blocked by verapamll, but not by UIC2, in a concentration-dependent manner. Conclusions: The differential HMVE-L uptake of fentanyl and alfentanil is consistent with the observed differences in the pulmonary uptake of these drugs. This suggests that specific fentanyl uptake and sequestration by HMVE-L cells may be the mechanisms of its extensive pulmonary uptake.

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