Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein.
BACKGROUND
The efflux transporter P-glycoprotein, a member of the adenosine triphosphate-binding cassette superfamily, is a major determinant of the pharmacokinetics and pharmacodynamics of the opioid loperamide, a well-recognized antidiarrheal agent. Animal studies indicate that P-glycoprotein limits morphine entry into the brain. In this study, the authors examined whether other opioids of importance to anesthesiologists such as fentanyl, sufentanil, and alfentanil, and also morphine-6-glucuronide and morphine-3-glucuronide, are P-glycoprotein substrates and whether, in turn, these opioids act also as P-glycoprotein inhibitors.


METHODS
The transcellular movement of the various opioids, including loperamide and morphine, was assessed in L-MDR1 (expressing P-glycoprotein) and LLC-PK1 cell monolayers (P-glycoprotein expression absent). A preferential basal-to-apical versus apical-to-basal transport in the L-MDR cells but not the LLC-PK1 cells is seen for P-glycoprotein substrates. In addition, the effect of the various opioids on the transcellular movement of the prototypical P-glycoprotein substrate digoxin was examined in Caco-2 cell monolayers. IC50 values were calculated according to the Hill equation.


RESULTS
Loperamide was a substrate showing high dependence on P-glycoprotein in that basal-apical transport was nearly 10-fold greater than in the apical-basal direction in L-MDRI cells. Morphine also showed a basal-to-apical gradient in the L-MDR1 cell monolayer, indicating that it too is a P-glycoprotein substrate, but with less dependence than loperamide in that only 1.5-fold greater basal-apical directional transport was observed. Fentanyl, sufentanil, and alfentanil did not behave as P-glycoprotein substrates, whereas the morphine glucuronides did not cross the cell monolayers at all, whether P-glycoprotein was present or not. Loperamide, sufentanil, fentanyl, and alfentanil inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells with IC50 values of 2.5, 4.5, 6.5, and 112 microm, respectively. Morphine and its glucuronides (20 microm) did not inhibit digoxin (5 microm) transport in Caco-2 cells, and therefore IC50 values were not determined.


CONCLUSIONS
Opioids have a wide spectrum of P-glycoprotein activity, acting as both substrates and inhibitors, which might contribute to their varying central nervous system-related effects.
Wandel
Christoph
C
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
Kim
Richard
R
Wood
Margaret
M
Wood
Alastair
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015760:Alfentanil / Q000378:metabolism* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D000930:Antidiarrheals / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008139:Loperamide / Q000378:metabolism* / Q000494:pharmacology; D009020:Morphine / Q000378:metabolism* / Q000494:pharmacology; D017409:Sufentanil / Q000378:metabolism* / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000930:Antidiarrheals; D015760:Alfentanil; D008139:Loperamide; D009020:Morphine; D017409:Sufentanil; D005283:Fentanyl