The log linear trapezoidal method with Vinorelbine p38 MAPK inhibitor extrapolation to infinite time was used to calculate the area under the plasma concentration time curve. The terminal elimination half life was calculated by ln2/, where is the terminal slope of the time vs. log concentration. Mean plasma domperidone concentration time curve following a single oral administration of 20 mg of domperidone with placebo or itraconazole are shown in Fig. 1, and pharmacokinetic parameters of domperidone are summarized in Table 1. Itraconazole coadministration significantly increased domperidone AUC0 and Cmax compared with placebo. No significant change was found in tmax or t1/2. Domperidone induced changes were evident in serum prolactin levels, but not in VAS and EEG. Mean serum prolactin levels reached the maximum 90 min after administration, and then gradually decreased over time. The concentration time curve of serumprolactin after coadministration of itraconazole was similar to that after placebo administration. None of the AUEs for VAS, EEG, and prolactin was significantly affected by coadministration of itraconazole. The range of 95% CI of the difference between prolactin AUEs in placebo and the itraconazole phase was from 4.0 to 7.5% of the AUE value in the placebo phase. This is within the range from 20 to 25%, indicating that AUE values of prolactin in both treatments can be considered to be equivalent. The plots of plasma domperidone concentration versus the serum prolactin level showed a counterclockwise relationship, indicating that the prolactin elevation lagged behind the plasma domperidone concentration. A concentration effect analysis described a linear correlation between prolactin response and the concentration of domperidone in the effect compartment. The correlation coefficients of the linear relationship in individual subjects ranged from 0.883 to 0.996.
Coadministration of itraconazole shifted the plots to the right. Estimated parameters of this model showed a significantly reduced responsiveness and a shortened equilibration half life when administered with itraconazole. Discussion Lapatinib 388082-77-7 This study showed that itraconazole, an inhibitor of CYP3A and MDR1, increased the AUC0 and Cmax of orally administered domperidone without affecting the t1/2. Domperidone is a substrate for CYP3A and MDR1 and is mainly metabolized by CYP3A. After oral administration, domperidone undergoes extensive first pass metabolism, and the bioavailability of oral domperidone is 13 17%. Unchanged domperidone excreted in urine accounts for0.5%. Taking these pharmacokinetic properties into account, the results of our study indicate that a reduced elimination by inhibition of CYP3A and/or MDR1 plays an important role in the changes in domperidonepharmacokinetics by itraconazole. However, the t1/2 of domperidone was not significantly altered by itraconazole, suggesting that the pharmacokinetic interaction observed in this study might take place mainly in the process of the first pass elimination. On the other hand, itraconazole produces a remarkable increase in AUC of the CYP3A substrates, midazolam and triazolam, with a significant prolongation of t1/2. Likewise, itraconazole increases the AUC of quinidine, a substrate of CYP3A and MDR1, with a prolongation of t1/2. Although the.