title: Domperidone interacts with pioglitazone but not with ondansetron via common CYP metabolism in vitro.
abstract: Domperidone (prokinetic agent) is frequently co-administered with pioglitazone (anitidiabetic) or ondansetron (antiemetic) in gastroparesis management. These drugs are metabolized via cytochome P-450 (CYP) 3A4, raising the possibility of interaction and adverse reactions. The concentration-dependent inhibitory effect of pioglitazone and ondansetron on domperidone hydroxylation was monitored in pooled human liver microsomes (HLM). Pioglitazone was further assessed as a mechanism-based inhibitor. Microsomal binding was evaluated in our assessment. In HLM, Vmax/Km estimates for monohydroxy domperidone formation decreased in presence of pioglitazone. Diagnostic plots indicated that pioglitazone inhibited domperidone in a partial mixed-type manner. The in vitro Ki was 1.52 µM. Predicted in vivo AUCi/AUC ratio was 1.98. Pioglitazone also exerted time-dependent inhibition on the metabolism of domperidone and the average remaining enzymatic activity decreased significantly upon preincubation with pioglitazone over 0-40 min. Diagnostic plots showed no inhibitory effect of ondansetron on domperidone hydroxylation. 6. In conclusion, pioglitazone inhibited domperidone metabolism in vitro through different complex mechanisms. Our in vitro data predict that the co-administration of these drugs can potentially trigger an in vivo drug-drug interaction.
authors.affiliation: Department of Pharmaceutical Sciences and.
authors.forename: Amir S
authors.initials: AS
authors.lastname: Youssef
authors.forename: Henry P
authors.initials: HP
authors.lastname: Parkman
authors.forename: Swati
authors.initials: S
authors.lastname: Nagar
mesh_terms: D000932:Antiemetics / Q000494:pharmacology; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004294:Domperidone / Q000494:pharmacology*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D017294:Ondansetron / Q000494:pharmacology*; D000077205:Pioglitazone; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000932:Antiemetics; D005765:Gastrointestinal Agents; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D017294:Ondansetron; D004294:Domperidone; D051544:Cytochrome P-450 CYP3A; D000077205:Pioglitazone
keywords: CYP3A4; domperidone; drug–drug interaction; ondansetron; pioglitazone