Ars in plasma behind the parent drug. Domperidone is Rolipram 61413-54-5 metabolized to hydroxylated and N dealkylated forms. The proportion of domperidone remaining unchanged in plasma is small, and approximately 86% of the AUC for total radioactivity is accounted for by its metabolites after oral administration of radio labeled domperidone. However, to our knowledge, no studies have examined the pharmacological activities of domperidone metabolites. Assuming that the metabolites of domperidone have pharmacological activity on dopamine receptors, even if the activity is weaker than the parent drug, the greater amount of metabolites in plasma may contribute to the net effect on the prolactin secretion. If the metabolites are active, the modeling procedure only with the parent drug can lead to an overestimation of the responsiveness to the drug and equilibrium half life. In that case, a model that incorporates effect compartments for both the parent drug and its metabolite is required In this study, itraconazole did not significantly affect the changes in prolactin levels produced by domperidone although itraconazole increased domperidone concentrations by approximately 3 fold. Itraconazole significantly altered parameters for the drug concentration prolactin level relationship. A reduced responsiveness and faster equilibrium at the effect site was observed when coadministered with itraconazole. A possibility of interactions between domperidone and itraconazole at receptor sites, e.g. competitive receptor binding, should be considered as one of the mechanisms for the altered responsiveness. It is not clear whether itraconazole binds to the dopamine receptor and has any effects on the pituitary function. However, ketoconazole, which is also an azole antimycotic drug, does not affect pituitary hormone levels, including prolactin.
Another possible explanation for the altered parameters of the domperidone concentration prolactin level relationship is again the formation of active metabolites. Provided that the metabolites are active, their decrease in plasma by CYP3A inhibition would attenuate the net increase in prolactin secretion. Together with the evident counterclockwise hysteresis observed in the placebo phase, the metabolites of domperidone may play a role in prolactin secretion, and the similarity of the domperidone induced elevation in the prolactin level between the placebo and the itraconazole Fulvestrant Estrogen/progestin receptor inhibitor phase may be attributable to a reduced formation of active metabolites. Further studies concerning the activity of domperidone metabolites are necessary. Domperidone is a substrate for MDR1, which accounts for its low distribution in the brain. This property of domperidone is likely to be associated with its fewer CNS side effects compared with metoclopramide. Inhibition of efflux transporter MDR1 in the brain may produce an increase in the distribution of domperidone to the brain and cause CNS side effects. Acute effects of dopamine D2 antagonism include extrapyramidal symptoms and EEG changes. There is a report that a single intravenous dose of metoclopramide caused akathisia in 6 out of 7subjects. In that study, one subject experienced moderately severe akathisia with an intense desire to move. However, in the present study, no such symptoms assessed by VAS.