THE GASTROPROKINETIC AND ANTIEMETIC DRUG METOCLOPRAMIDE IS A SUBSTRATE AND INHIBITOR OF CYTOCHROME P450 2D6 Z. DESTA, G. M. WU, A. M. MOROCHO, AND D. A. FLOCKHART Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington, DC (Received June 25, 2001; accepted November 27, 2001) This article is available online at http://dmd.aspetjournals.org ABSTRACT: Metoclopramide is increasingly prescribed for conditions previ- ously treated with cisapride, but its metabolic enzymology and drug interactions are poorly understood. Using human liver micro- somes (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 meto- clopramide to inhibit the P450 system, using isoform-specific sub- strate reaction probes of CYP1A2, 2C19, 2C9, 2D6, 2E1, and 3A4. Metoclopramide was predominantly N-dealkylated to monodeeth- ylmetoclopramide, a metabolite that has not so far been described in humans. Formation rate of this metabolite followed Michaelis- Menten kinetics (K m , 68  16 M; V max , 183  57 pmol/min/mg of protein; n  3 HLMs). Of the isoform-specific inhibitors tested, 1 M quinidine was a potent inhibitor of metoclopramide (25 M) monodeethylation [by an average of 58.2%; range, 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 M; range, 0.15 M in HL66, 2.4 M in HL09-14-99, and 5.7 M in HLD). Except trolean- domycin, 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 K m value de- rived (53 M) was close to that from HLMs (68 M). Metoclopramide is a potent inhibitor of CYP2D6 at therapeutically relevant concentra- tions (K i  4.7  1.3 M), with negligible effect on other isoforms tested. Further inhibition of CYP2D6 was observed when metoclopra- mide 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 M), suggesting mecha- nism-based inhibition. Metoclopramide elimination is likely to be slowed in poor metabolizers of CYP2D6 or in patients taking inhibi- tors of this isoform, whereas metoclopramide itself could reduce the clearance of CYP2D6 substrate drugs. Metoclopramide, since its introduction in the 1960s, is a frequently prescribed drug in adults and children as an antiemetic and for preventing vomiting induced by antineoplastic drugs, particularly cisplatin (Albibi and McCallum, 1983). In addition, it has been widely used as a gastrointestinal (GI 1 ) prokinetic drug to control symptoms of upper GI motor disorders, such as those seen in gastroesophageal reflux disease, dyspepsia, and diabetic gastroparesis (Albibi and Mc- Callum, 1983; Harrington et al., 1983). Because of the neurological adverse effects of metoclopramide that may occur in up to 20% of patients (Albibi and McCallum, 1983), the use of this drug as a prokinetic has been largely limited after the introduction of cisapride in 1989, a drug that was deemed superior in terms of efficacy and CNS safety (McCallum et al., 1988). However, the use of cisapride has now been restricted in the United States and other countries due to its ability to bring about potentially fatal arrhythmia, leaving a gap in the armamentarium available for treating GI motility disorders. Because no new prokinetic drug is available to replace cisapride, a rapid shift toward the use of older prokinetic agents such as domperidone, erythromycin, and metoclopramide may follow. The increase in the number of deaths due to cisapride, how- ever, raises the disturbing possibility that other prokinetics, including metoclopramide, may have similar effects, in the same way as a number of other antihistamines were shown to be cardiotoxic after the initial reports with terfenadine (Woosley, 1996; Wang et al., 1998). In those studies, metabolic drug interaction was found to be an important risk (Dresser et al., 2000; Michalets and Williams, 2000) as it could be also in the use of domperidone and erythromycin as prokinetic drugs. Domperidone and erythromycin carry proarrhythmic properties (Drici et al., 1998; Drolet et al., 2000), and erythromycin is a known CYP3A inhibitor with the potential of multiple drug interactions (for review, see Dresser et al., 2000). Because of these concerns, metoclopramide as an alternative to cisapride in adults and children has to be seriously considered, but it too has a questionable safety record. Metoclopramide has been asso- ciated with severe adverse effects in the central nervous system, including extrapyramidal symptoms, dystonia, and even death, and there appears to be a correlation between plasma concentrations of metoclopramide and most CNS adverse effects except dystonia This study was supported by the National Institute of General Medical Sci- ences Grants R01-GM56898-01 and T32-GM56898. 1 Abbreviations used are: GI, gastrointestinal; P450, cytochrome P450; HLMs, human liver microsomes; HPLC, high-performance liquid chromatography; CNS, central nervous system. Address correspondence to: Dr. Zeruesenay Desta, Department of Medicine/ Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, West Outpatient Building 320, 1001 West 10th St., Indianap- olis, IN 46202-2879. E-mail: zdesta@iupui.edu 0090-9556/02/3003-336–343$3.00 DRUG METABOLISM AND DISPOSITION Vol. 30, No. 3 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 500/964304 DMD 30:336–343, 2002 Printed in U.S.A. 336 at ASPET Journals on April 13, 2017 dmd.aspetjournals.org Downloaded from