Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine

Br J Clin Pharmacol. 2010 May;69(5):498-507. doi: 10.1111/j.1365-2125.2010.03616.x.


Aim: Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug-drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate).

Methods: Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination.

Results: When gabapentin enacarbil was co-administered with naproxen, gabapentin C(ss,max) increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUC(ss) increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated.

Conclusions: No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biological Transport
  • Carbamates / administration & dosage
  • Carbamates / adverse effects
  • Carbamates / pharmacokinetics*
  • Cimetidine / administration & dosage
  • Cimetidine / adverse effects
  • Cimetidine / pharmacokinetics*
  • Constipation / chemically induced
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Interactions
  • Dyspepsia / chemically induced
  • Fatigue / chemically induced
  • Humans
  • Male
  • Middle Aged
  • Naproxen / administration & dosage
  • Naproxen / adverse effects
  • Naproxen / pharmacokinetics*
  • Prodrugs
  • Young Adult
  • gamma-Aminobutyric Acid / administration & dosage
  • gamma-Aminobutyric Acid / adverse effects
  • gamma-Aminobutyric Acid / analogs & derivatives*
  • gamma-Aminobutyric Acid / pharmacokinetics


  • 1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid
  • Carbamates
  • Drug Combinations
  • Prodrugs
  • gamma-Aminobutyric Acid
  • Naproxen
  • Cimetidine