The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6.

Metoclopramide is increasingly prescribed for conditions previously treated with cisapride, but its metabolic enzymology and drug interactions are poorly understood. Using human liver microsomes (HLMs) and recombinant human cytochromes P450 (P450), we identified the major route of metoclopramide oxidation and the P450 isoforms involved. We also documented the ability of metoclopramide to inhibit the P450 system, using isoform-specific substrate reaction probes of CYP1A2, 2C19, 2C9, 2D6, 2E1, and 3A4. Metoclopramide was predominantly N-dealkylated to monodeethylmetoclopramide, a metabolite that has not so far been described in humans. Formation rate of this metabolite followed Michaelis-Menten kinetics (K(m), 68 +/- 16 microM; V(max), 183 +/- 57 pmol/min/mg of protein; n = 3 HLMs). Of the isoform-specific inhibitors tested, 1 microM quinidine was a potent inhibitor of metoclopramide (25 microM) monodeethylation [by an average of 58.2%; range, approximately 38% (HL09-14-99) to 78.7% (HL161)] with K(i) values highly variable among the HLMs tested (K(i), mean +/- S.D., 2.7 +/- 2.8 microM; range, 0.15 microM in HL66, 2.4 microM in HL09-14-99, and 5.7 microM in HLD). Except troleandomycin, which inhibited metoclopramide metabolism in only one HLM (by approximately 23% in HL09-14-99), the effect of other inhibitors was minimal. Among the recombinant human P450 isoforms examined, monodeethylmetoclopramide was formed at the highest rate by CYP2D6 (V = 4.5 +/- 0.3 pmol/min/pmol of P450) and to a lesser extent by CYP1A2 (0.97 +/- 0.15 pmol/min/pmol of P450). The K(m) value derived (approximately 53 microM) was close to that from HLMs (68 microM). Metoclopramide is a potent inhibitor of CYP2D6 at therapeutically relevant concentrations (K(i) = 4.7 +/- 1.3 microM), with negligible effect on other isoforms tested. Further inhibition of CYP2D6 was observed when metoclopramide was preincubated with HLMs and NADPH-generating system before the substrate probe was added (maximum rate of inactivation, K(inact) = 0.02 min(-1), and the concentration required to achieve the half-maximal rate of inactivation, K'(i) = 0.96 microM), suggesting mechanism-based inhibition. Metoclopramide elimination is likely to be slowed in poor metabolizers of CYP2D6 or in patients taking inhibitors of this isoform, whereas metoclopramide itself could reduce the clearance of CYP2D6 substrate drugs.