Metabolic interactions between prokinetic agents domperidone and erythromycin: an in vitro analysis.
This study examined in vitro interaction between domperidone and erythromycin. Both are prescribed for refractory gastroparesis. Domperidone is metabolized via human cytochrome P4503A4. Erythromycin is a CYP3A4 inhibitor. Incubations evaluated domperidone metabolite formation in human liver microsomes and recombinant CYP3A4. Concentration- and time-dependent inhibition of 500 microM domperidone was studied with 2.5-200 microM erythromycin over 10-40 min. Domperidone metabolite (5-hydroxy domperidone, M3) formation was inhibited by erythromycin in a concentration- and time-dependent manner. The K(I) estimate was 18.4 microM in human liver microsomes and 4.1 microM in CYP3A4. Using a model incorporating CYP3A4 hepatic and gut inhibition, in vitro estimates from human liver microsomes and CYP3A4 were used to predict in vivo AUCi/AUC ratios of 2.54 and 4.95, respectively. Significant inhibition of domperidone metabolism by erythromycin occurs. This predicts greater domperidone drug exposure when used with erythromycin. This important drug-drug interaction will be evaluated in future human studies.
Ung
D
D
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Parkman
H P
HP
Nagar
S
S
D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004294:Domperidone / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D004917:Erythromycin / Q000493:pharmacokinetics* / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011994:Recombinant Proteins / Q000378:metabolism
D018492:Dopamine Antagonists; D005765:Gastrointestinal Agents; D011994:Recombinant Proteins; D004294:Domperidone; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human