P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans.
OBJECTIVE
Increased bioavailability of the P-glycoprotein (Pgp) substrates digoxin and cyclosporin due to erythromycin has been observed in vivo. The aim of the present study was to investigate the effect of orally administered erythromycin on the oral bioavailability of the beta-blocker talinolol. Talinolol is a suitable model compound for Pgp drug-drug interaction studies due to its Pgp-related active intestinal secretion and lack of any significant metabolism.


METHODS
In a randomized crossover study, the oral pharmacokinetics of talinolol (50 mg) after a concomitant single oral dose of erythromycin (2 g) or placebo were investigated in 9 healthy men. Concentrations of talinolol were measured in serum and urine by HPLC.


RESULTS
The area under the curve of talinolol serum concentrations from 0 to 24 h (AUC(0-24)) and the maximum serum concentrations (Cmax) were significantly increased after administration of erythromycin compared to placebo. t(max) values were significantly reduced. The renal clearance (CLR) of talinolol was unchanged after co-administration of erythromycin and there was a small but statistically significant decrease in elimination half-life (t1/2). Serum pharmacokinetics correlate with the results derived from urine concentration measurement. One subject suffered from moderate diarrhea after erythromycin and was excluded from the analysis.


CONCLUSIONS
We suggest that the increase in oral bioavailability of talinolol after concomitant erythromycin is caused by increased intestinal net absorption due to Pgp inhibition by erythromycin.
Schwarz
U I
UI
Institute of Clinical Pharmacology, Faculty of Medicine, University of Technology, Dresden, Germany.
Gramatté
T
T
Krappweis
J
J
Oertel
R
R
Kirch
W
W
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology*; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000900:Anti-Bacterial Agents; D005765:Gastrointestinal Agents; D006023:Glycoproteins; D011412:Propanolamines; D011500:Protein Synthesis Inhibitors; C011550:talinolol; D004917:Erythromycin