| Aims: To investigate whether metoclopramide has an inhibitory effect on in vivo activity of CYP2D6, and to evaluate whether the possible inhibition is CYP2D6 genotype related, namely whether the inhibition extent in different genotypes has a significant difference.Methods: 17 unrelated Chinese Han male volunteers were recruited in the study. 10 mg metoclopramide was administered three times daily for three consecutive days (day 2 to day4) . The activity of CYP2D6 was evaluated at day 1 (baseline), day 5 (after oral administration of metoprolol) and day 12 (after 1 week washout period). The index for CYP2D6 activity was the value of lgMR(MT/ a -OH-MT) in 0-8 hour urine after oral administration of lOOmg metoprolol. 5ml peripheral venous blood was collected for DNA extraction, and further to genotype CYP2D6.Results: The activity of CYP2D6 (mean±SE) at baseline was significantly different between CYP2D6*1/*1 and CYP2D6*10/*10 individuals (-I.0fcb0.ll versus -0.29±0.10, P<0.01), namely there existed a gene dose effect. Multiple dose metoclopramide significantly inhibited the activity of CYP2D6, IgMR value increased from -1.06±0.11 to -0.78±0.11 (P<0.01), -0.29±0.10 to -0.13±0.11 (P<0.01) for the CYP2D6*1/*J and CYP2D6*10/*10 genotypes, respectively. In the wild type homozygous individuals, after one week's washout period, the 1gMR value decreased to -1.27±0.08, significantly different compared with the baseline value (P<0.05). The ratios of MR value [median (P25, P75)] between day5 and dayl were 74.65 (48.6. 75.5) and 40.2 (19.3, 58.8) (P<0.05).Conclusions: Metoclopramide inhibited the in vivo activity of CYP2D6, and the inhibition was CYP2D6 genotype related, with the inhibition being more prominent in CYP2D6*1/*l individuals. When metoclopramide was coadministered with the substrates of CYP2D6 in clinical practice, attention should be paid to avoid possible drug interactions. In addition, we'd better evaluate the interaction combined with the effect of genotype. |
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