How is gabapentin enacarbil (Gabapentin) metabolized?

Metabolism of Gabapentin Enacarbil

Gabapentin enacarbil is a prodrug that is rapidly hydrolyzed to gabapentin after absorption and is not appreciably metabolized in humans, with gabapentin being primarily eliminated unchanged through renal excretion. 1, 2

Absorption and Conversion to Gabapentin

• Gabapentin enacarbil is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1) 2
• Unlike gabapentin, which has variable and dose-dependent bioavailability, gabapentin enacarbil provides predictable and dose-proportional gabapentin exposure 3
• After absorption, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is the active compound 2

Metabolism and Elimination

• Gabapentin (derived from gabapentin enacarbil) is not appreciably metabolized in humans 1
• All pharmacological actions following gabapentin enacarbil administration are due to the activity of the parent compound gabapentin 1
• Elimination occurs primarily through renal excretion as unchanged drug 1, 3
• Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing 1

Pharmacokinetic Considerations

• Gabapentin plasma clearance is directly proportional to creatinine clearance 1, 3
• In patients with renal impairment, gabapentin clearance decreases proportionally with decreasing creatinine clearance 3
• An approximately 1.6-fold decrease in oral clearance occurs for every 2-fold decrease in creatinine clearance 3
• Less than 3% of gabapentin circulates bound to plasma protein 1

Drug Interactions

• When gabapentin enacarbil was co-administered with naproxen (an MCT-1 substrate), gabapentin maximum concentration increased by approximately 8% and AUC by 13% 2
• Co-administration with cimetidine (an OCT2 substrate) increased gabapentin AUC by 24% and decreased renal clearance of gabapentin 2
• Unlike some other medications, gabapentin derived from gabapentin enacarbil does not induce hepatic enzymes or interact with the cytochrome P450 system 4, 5

Special Populations

• In elderly patients, gabapentin plasma clearance is reduced 1
• Apparent oral clearance (CL/F) of gabapentin decreases as age increases, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age 1
• In patients with end-stage renal disease on hemodialysis, approximately 35% of gabapentin can be removed during a 4-hour hemodialysis session 6
• Dosage adjustment is necessary for patients with impaired renal function 3

Clinical Implications

• The lack of hepatic metabolism means that gabapentin enacarbil has minimal drug-drug interactions compared to medications metabolized by the liver 4, 5
• Renal function should be assessed when prescribing gabapentin enacarbil, as dosage adjustments are necessary in patients with renal impairment 3
• The predictable pharmacokinetics of gabapentin enacarbil allows for more reliable dosing compared to immediate-release gabapentin 3