Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6

Livezey, Mara R.; Briggs, Erran D.; Bolles, Amanda K.; Nagy, Leslie D.; Fujiwara, Rina; Furge, Laura Lowe

doi:10.3109/00498254.2013.835885

Cited by 42 publications

(40 citation statements)

References 27 publications

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“…49 Ciprofloxacin is reportedly excreted via transintestinal excretion but not into bile. Only for tiotropium (CYP2D6, 3A4) 52 and metoclopramide (CYP2D6, 1A2, 2C9, 2C19, 3A4) 50 are the catabolizing enzymes, and for avibactam the involved organic anion transporters 53 known. Only for tiotropium (CYP2D6, 3A4) 52 and metoclopramide (CYP2D6, 1A2, 2C9, 2C19, 3A4) 50 are the catabolizing enzymes, and for avibactam the involved organic anion transporters 53 known.…”

Section: Available Datamentioning

confidence: 99%

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration

Hinderling

2018

Clinical Pharm in Drug Dev

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The investigation identified 10 publications that reported the individual values of total clearance (CL), renal clearance (CLr), nonrenal clearance (CLnr), and the glomerular filtration rate (GFR), in subjects with varying renal functions. We used these data to estimate extent and prevalence of changes in CLnr in chronic kidney disease (CKD) by examining the relationship between clearances and renal function. The investigation was restricted to drugs given intravenously and eliminated by mixed renal and nonrenal pathways. Six drugs showed a significant reduction of CLnr of 61% to 63% in subjects with severe renal impairment, suggesting that the decline of CLnr in advanced CKD can be clinically relevant and may not be uncommon. The decline of CLnr in CKD for these 6 drugs is linearly correlated with the decline of CLr. With 4 of the drugs studied, a significant reduction of CLnr in CKD was not seen. Renal clearance is a more reliable measure of renal function than GFR assessed by creatinine clearance. Chronic kidney disease affects the elimination more than the distribution of the 10 drugs.

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Section: Available Datamentioning

confidence: 99%

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration

Hinderling

2018

Clinical Pharm in Drug Dev

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“…Several researches have indicated that the absorption of metoclopramide in small intestinal mucosa was mainly mediated by P-gp, and metoclopramide was mainly metabolized by CYP2D6. [19][20][21] Therefore, the potential drug-drug interaction of metoclopramide mediated by CYP450 and P-gp might happen.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Drug-diet interaction between Psidium guajava (Guava) fruit and Metoclopramide

Amadi

Aghalibe

2019

J. Drug Delivery Ther.

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Studies have showed that phytochemicals present in fruit juices alter the oral bioavailability of drugs by inhibition of metabolising enzymes and transport proteins. The present study aimed to investigate the effect of Psidium guajava on the oral exposure of metoclopramide in rabbits. Pharmacokinetic parameters of metoclopramide were determined in rabbits following an oral (0.5mg/kg) administration of metoclopramide in the presence and absence of Psidium guajava (5mL/kg, given orally). Compared to the control group given metoclopramide alone, the combined use of Psidium guajava increased the oral exposure (AUC) of metoclopramide by 13% with a corresponding 177 % increase in Cmax and half-life (71%). Furthermore, Tmax decreased from 2h to 1h which might have contributed to the elevated plasma drug concentration in the first two hours in the presence of Psidium guajava. There was a significant increase in Cmax (177%) and Ka (207%) which could be attributed to enhanced absorption via inhibition of P-gp resulting to increased bioavailability of the drug. In contrast, there was a significant decrease in elimination rate (88%) and a decrease in clearance rate (17%) attributable to inhibitor of P450 enzymes (CYP2D6) by the phytochemical constituents. Psidium guajava enhanced the oral exposure of metoclopramide in rabbits likely by the inhibition of P-glycoprotein-mediated efflux during the intestinal absorption and inhibition of P450 enzyme system during metabolism, suggesting that the combined use of Psidium guajava or Psidium guajava-containing diet with metoclopramide may require close monitoring for potential drug–diet interactions. Keywords: metoclopramide, Psidium guajava, diet–drug interaction, P-glycoprotein, P450 enzymes.

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“…In similar metabolism experiments with CYP3A4, mono-oxygenation of SCH 66712 at four different positions was apparent by the presence of four distinct m/z 355 ions in the mass spectral analysis (M+1). To determine whether mono-oxygenation was on carbon or nitrogen atoms, titanium trichloride (TiCl 3 ) was used to selectively reduce any hydroxylamines as previously described elsewhere (Seto and Guengerich, 1993;Kulanthaivel et al, 2004;Livezey et al, 2014). Because the metabolites formed by CYP3A4 and by CYP2D6 were the same, the metabolites as formed by CYP2D6 were used in the TiCl 3 experiments due to the more uniform distribution of products (as compared with CYP3A4) and therefore ease of comparison of changes upon HCl or TiCl 3 treatment (vide infra).…”

Section: Methodsmentioning

confidence: 99%

“…A control sample not treated with TiCl 3 or HCl was placed on ice for 1 hour. All samples were then centrifuged, and the supernatant was analyzed by LC-ESI-MS as described previously (Nagy et al, 2011;Livezey et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

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Mechanism-Based Inactivation of Human Cytochrome P450 3A4 by Two Piperazine-Containing Compounds

et al. 2014

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Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of more than half of pharmaceutic drugs, and inactivation of CYP3A4 can lead to adverse drug-drug interactions. The substi-(EMTPP) have been previously identified as mechanism-based inactivators (MBI) of CYP2D6. The present study shows that both SCH 66712 and EMTPP are also MBIs of CYP3A4. Inhibition of CYP3A4 by SCH 66712 and EMTPP was determined to be concentration, time, and NADPH dependent. In addition, inactivation of CYP3A4 by SCH 66712 was shown to be unaffected by the presence of electrophile scavengers. SCH 66712 displays type I binding to CYP3A4 with a spectral binding constant (K s ) of 42.9 6 2.9 mM. The partition ratios for SCH 66712 and EMTPP were 11 and 94, respectively. Whole protein mass spectrum analysis revealed 1:1 binding stoichiometry of SCH 66712 and EMTPP to CYP3A4 and a mass increase consistent with adduction by the inactivators without addition of oxygen. Heme adduction was not apparent. Multiple monooxygenation products with each inactivator were observed; no other products were apparent. These are the first MBIs to be shown to be potent inactivators of both CYP2D6 and CYP3A4.

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Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6

Cited by 42 publications

References 27 publications

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration

Quantitative Assessment of the Effect of Chronic Kidney Disease on the Nonrenal Clearance of 10 Drugs After Intravenous Administration

Evaluation of Drug-diet interaction between Psidium guajava (Guava) fruit and Metoclopramide

Mechanism-Based Inactivation of Human Cytochrome P450 3A4 by Two Piperazine-Containing Compounds

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