How is Reglan (metoclopramide) metabolized in the body?

Metabolism of Reglan (Metoclopramide)

Metoclopramide is primarily metabolized by CYP2D6 through N-deethylation and N-hydroxylation pathways, with approximately 85% of an oral dose eliminated in the urine within 72 hours, half as free or conjugated drug. 1, 2

Primary Metabolic Pathways

CYP2D6 is the dominant enzyme responsible for metoclopramide metabolism, catalyzing two major oxidative reactions 2, 3:

• N-deethylation to form monodeethylmetoclopramide (the predominant metabolite, previously undescribed in humans until 2002) 2
• N-hydroxylation on the phenyl ring amine 3
• The Km for N-deethylation is approximately 53-68 µM, indicating metabolism occurs at therapeutically relevant concentrations 2, 3

Secondary metabolic pathways involve other CYP isoforms to a lesser extent 2, 3:

• CYP1A2 contributes modestly (formation rate ~0.97 pmol/min/pmol P450 versus 4.5 for CYP2D6) 2
• CYP2C9, CYP2C19, and CYP3A4 play minor roles 3
• N-4 sulfate conjugation is an important non-oxidative pathway in humans 4

Pharmacokinetic Parameters

Absorption and distribution characteristics 1, 4:

• Oral bioavailability: 80% ± 15.5% (range 32-100% due to variable first-pass metabolism) 1, 4
• Peak plasma concentrations occur 1-2 hours after oral dosing 1
• Volume of distribution: ~3.5 L/kg, indicating extensive tissue distribution 1, 5
• Plasma protein binding: ~30% 1

Elimination parameters 1, 5, 4:

• Half-life: 5-6 hours in patients with normal renal function 1
• Total body clearance: 0.31-0.69 L/kg/h 5
• Approximately 85% eliminated in urine within 72 hours 1
• About 50% of urinary excretion is free or conjugated metoclopramide 1
• Only 3-6% excreted as unchanged parent drug 1

Clinical Implications for Special Populations

Renal impairment significantly affects clearance 1:

• Creatinine clearance <40 mL/min requires dose reduction to approximately one-half the standard dose 1
• Plasma clearance, renal clearance, and non-renal clearance all decrease proportionally with declining renal function 1
• Elimination half-life increases in renal impairment despite renal clearance accounting for only 20% of total clearance in normal patients 1, 4

Hepatic impairment considerations 1:

• Metoclopramide undergoes minimal hepatic metabolism except for simple conjugation 1
• Safe use has been described in patients with advanced liver disease when renal function is normal 1

CYP2D6 poor metabolizers face critical risks 2, 3:

• Metoclopramide elimination will be substantially slowed in CYP2D6 poor metabolizers 2
• This population may experience drug accumulation and increased risk of extrapyramidal side effects 2
• Consider genetic testing or lower initial doses in patients with suspected CYP2D6 deficiency 2

Drug Interaction Profile

Metoclopramide is a potent CYP2D6 inhibitor 2, 3:

• Ki = 4.7 ± 1.3 µM for reversible inhibition 2
• Inhibition occurs at therapeutically relevant concentrations 2
• Contrary to earlier reports, metoclopramide is NOT a mechanism-based inactivator of CYP2D6 3
• Can reduce clearance of other CYP2D6 substrate drugs 2

Negligible effects on other CYP isoforms 2:

• Minimal inhibition of CYP1A2, 2C9, 2C19, 2E1, and 3A4 2
• Drug interactions primarily concern CYP2D6 substrates only 2

Common Pitfalls and Caveats

Avoid these critical errors:

• Do not use standard doses in renal impairment (CrCl <40 mL/min) without reducing to half-dose, as both renal and non-renal clearance decrease disproportionately 1, 4
• Do not assume hepatic disease requires dose adjustment unless renal function is also compromised 1
• Do not overlook CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine) that can dramatically increase metoclopramide levels and extrapyramidal reaction risk 2
• Do not dismiss the risk in CYP2D6 poor metabolizers, who may develop toxicity at standard doses 2