Role of p-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmacoepidemiological studies.
OBJECTIVE
We determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin.


METHODS
In vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients.


RESULTS
All macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC(50)) values of 1.8, 4.1, 15.4, 21.8 and 22.7 micromol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 +/- 0.6 vs 0.9 +/- 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05).


CONCLUSIONS
Macrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.
Eberl
Sonja
S
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.
Renner
Bertold
B
Neubert
Antje
A
Reisig
Mareike
M
Bachmakov
Iouri
I
König
Jörg
J
Dörje
Frank
F
Mürdter
Thomas E
TE
Ackermann
Andreas
A
Dormann
Harald
H
Gassmann
Karl G
KG
Hahn
Eckhart G
EG
Zierhut
Stefanie
S
Brune
Kay
K
Fromm
Martin F
MF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001692:Biological Transport; D018938:Caco-2 Cells; D003404:Creatinine / Q000097:blood; D004074:Digitoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006331:Heart Diseases / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007297:Inpatients; D007444:Inulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D048628:Ketolides / Q000008:administration & dosage / Q000493:pharmacokinetics; D018942:Macrolides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D017891:Pharmacoepidemiology / Q000379:methods
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D048628:Ketolides; D018942:Macrolides; D004917:Erythromycin; D004077:Digoxin; D007444:Inulin; D003404:Creatinine; D004074:Digitoxin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C106791:telithromycin; D001663:Bilirubin