Background: Metoclopramide is metabolized by various cytochrome P450 (CYP) enzymes such as
CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Rifampicin is a non-selective inducer of P-glycoprotein
(P-gp) and CYP enzymes such as CYP3A4 and others.
Objective: This study was aimed at the evaluation of rifampicin’s enzyme induction effect on the pharmacokinetic
parameters of orally administered metoclopramide.
Method: This randomized, single-blind, two-phase cross-over pharmacokinetic study separated by a 4-week washout
period was conducted at a single center in Pakistan. It involved twelve Pakistani healthy male volunteers (nonsmokers)
divided into two groups. In the reference phase, each volunteer received a single oral dose of 20 mg
metoclopramide (Maxolon 10 mg, GlaxoSmithKline, Pakistan), while in the rifampicin-treated phase, each volunteer
received 600 mg rifampicin once daily for 6 days through oral route. On day 6, metoclopramide (20 mg) was
administered 2 hours after the last pretreatment dose of rifampicin. The serial blood samples were collected on
predetermined time points (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 18 h) and analyzed using a validated HPLC
method for the determination of pharmacokinetic parameters, i.e. Cmax, Tmax, and AUC0-∞ of metoclopramide. The
whole study was monitored by an unblinded clinician for the purpose of volunteer’s health safety.
Results: All the volunteers participated in the study until the end. Twelve healthy Pakistani males having mean age
26.0 (range 20.6-34.1) years and body mass index 25.1 (range 16.2-31.5) kg/m2 were included in this study after
taking written informed consent. Rifampicin significantly (P<0.05) decreased the mean Cmax, AUC0-∞ and T1/2 of
metoclopramide by 35%, 68%, and 44%, respectively. The laboratory tests did not reveal any significant change in
the biochemical, physical, hematological, or urinalytical values before and after metoclopramide treatment. None of
the volunteers complained of any discomfort during the study.
Conclusion: Rifampicin noticeably decreased the concentration of plasma metoclopramide. These results give in
vivo confirmation of the CYP3A4 involvement in the metoclopramide metabolism, in addition to CYP2D6.
Therefore, metoclopramide pharmacokinetics may be clinically affected by rifampicin and other potent enzyme