Difference in the result of t1/2 is not clear, it seems that the reduced firstpass elimination in the intestine, where MDR1 is abundantly Syk inhibitor in clinical trials expressed, plays a key role in the interaction observed in the current study. In an in vitro study using Caco 2 cells, domperidone showed the greatest transport ratio among 33 MDR1 substrates including quinidine. Domperidone may be one of the drugs that are highly susceptible to altered MDR1 function in the intestine. However, itraconazole alsoinhibits MDR1 mediated transport in renal tubular cells. Data shown in the present study were only the pharmacokinetics obtained from plasma parent drug concentrations after oral administration. To elucidate the main organ in which the interaction between itraconazole and domperidone occurs and to distinguish the effects of CYP3A from the effects of MDR1, further studies designed to determine changes in the bioavailability and metabolic/renal clearance of domperidone are necessary. Contribution of other CYPs, such as CYP1A2 and 2D6, might have affected the extent of alteration in the pharmacokinetics of domperidone, although these enzymes seem to play minor roles in the metabolism of domperidone. Dopamine antagonists, including domperidone, commonly induce an elevation of the serum/plasma prolactin level. In this study, maximum concentrations of prolactin occurred at 90 min, and the prolactin level gradually decreased over time after oral administration of domperidone. This time course change in prolactin levels is consistent with previous studies. Counterclockwise hysteresis was evident in the relationship between plasma domperidone concentration and serum prolactin level, showing that the prolactin elevation lags behind the plasma domperidone concentration. To describe the delayed time course of the effect, we used an effect compartment model, and the estimated effect site concentrations were linked to a linear concentration effect model. Emax or sigmoid Emax models are also used to analyze concentration effect relationships.
These models require estimation of maximal pharmacological effect. However, there was no evidence that a maximum effect was being reached in the dosage of domperidone used in the present study. In such a case, Emax and sigmoid Emax models cannot be fitted properly to data and can give false GSK-3 Inhibitors Emax and EC50 values. In the present study, the hysteresis loops were effectively collapsed by the modeling procedures incorporating an equilibration delay between the plasma and the hypothetical effect site concentrations of domperidone. The equilibrium half life derived from keo was 12.9 min. The mechanism of the delay is not established, but may arise from the time taken to reach the effect site and cellular processes leading to the effect. An equilibrium state of domperidone in the brain may be delayed because of reduced penetration across the blood brain barrier where the efflux transporter MDR1 is abundantly expressed. However, since the pituitary is located outside of the blood brain barrier, it is thought that an equilibration of domperidone in the pituitary is probably achieved earlier than in other regions of the brain. Another possible explanation for this delayed response is the formation of an active metabolite, which usually appe.
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