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Xenobiotica
the fate of foreign compounds in biological systems
Volume 44, 2014 - Issue 9
273
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Research Article

Domperidone interacts with pioglitazone but not with ondansetron via common CYP metabolism in vitro

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Pages 792-803 | Received 06 Jan 2014, Accepted 25 Feb 2014, Published online: 18 Mar 2014
 

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 1.52 µM. 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 0–40 min.

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.

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