RT Journal Article
SR Electronic
T1 The Gastroprokinetic and Antiemetic Drug Metoclopramide Is a Substrate and Inhibitor of Cytochrome P450 2D6
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 336
OP 343
DO 10.1124/dmd.30.3.336
VO 30
IS 3
A1 Z. Desta
A1 G. M. Wu
A1 A. M. Morocho
A1 D. A. Flockhart
YR 2002
UL http://dmd.aspetjournals.org/content/30/3/336.abstract
AB 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 predominantlyN-dealkylated to monodeethylmetoclopramide, a metabolite that has not so far been described in humans. Formation rate of this metabolite followed Michaelis-Menten kinetics (Km, 68 ± 16 μM;Vmax, 183 ± 57 pmol/min/mg of protein;n = 3 HLMs). Of the isoform-specific inhibitors tested, 1 μM quinidine was a potent inhibitor of metoclopramide (25 μM) monodeethylation [by an average of 58.2%; range, ∼38% (HL09-14-99) to 78.7% (HL161)] with Kivalues highly variable among the HLMs tested (Ki, mean ± S.D., 2.7 ± 2.8 μM; range, 0.15 μM in HL66, 2.4 μM in HL09-14-99, and 5.7 μM in HLD). Except troleandomycin, which inhibited metoclopramide metabolism in only one HLM (by ∼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 Km value derived (∼53 μM) was close to that from HLMs (68 μM). Metoclopramide is a potent inhibitor of CYP2D6 at therapeutically relevant concentrations (Ki = 4.7 ± 1.3 μM), 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, Kinact = 0.02 min−1, and the concentration required to achieve the half-maximal rate of inactivation, K′i= 0.96 μM), 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. The American Society for Pharmacology and Experimental Therapeutics