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Citation |
Youssef AS, Parkman HP, Nagar S. Xenobiotica 2014; 44(9): 792-803. |
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Copyright |
(Copyright © 2014, Informa - Taylor and Francis Group) |
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DOI |
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PMID |
unavailable |
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Abstract |
1. 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. 2. 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. 3. 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 1.52μM. Predicted in vivo AUCi/AUC ratio was 1.98. 4. Pioglitazone also exerted time-dependent inhibition on the metabolism of domperidone and the average remaining enzymatic activity decreased significantly upon preincubation with pioglitazone over 0-40min. 5. 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. © 2014 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted. Language: en |
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Keywords |
Humans; human; Drug Interactions; Chromatography, Liquid; Tandem Mass Spectrometry; Hypoglycemic Agents; Drug-Related Side Effects and Adverse Reactions; article; controlled study; drug metabolism; liquid chromatography; human cell; area under the curve; enzyme activity; cytochrome P450 3A4; antidiabetic agent; metabolism; drug clearance; antiemetic agent; suicide substrate; Antiemetics; drug interaction; in vitro study; in vivo study; drug inhibition; ondansetron; gastrointestinal agent; tandem mass spectrometry; evaluation study; Gastrointestinal Agents; CYP3A4; Cytochrome P-450 CYP3A; liver microsome; Hydroxylation; 2,4 thiazolidinedione derivative; pioglitazone; hydroxylation; Thiazolidinediones; Ondansetron; Drug-drug interaction; domperidone; adverse drug reaction; Microsomes, Liver; drug effects; cytochrome P450 3A; Domperidone; drug hydroxylation; Pioglitazone |