XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters
- 14 May 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 311 (1), 315-323
- https://doi.org/10.1124/jpet.104.067934
Abstract
Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in the upper small intestine. Saturation of this transporter at doses used clinically leads to dose-dependent pharmacokinetics and high interpatient variability, potentially resulting in suboptimal drug exposure in some patients. XP13512 [(±)-1-([(α-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed throughout the intestine by high-capacity nutrient transporters. XP13512 was stable at physiological pH but rapidly converted to gabapentin in intestinal and liver tissue from rats, dogs, monkeys, and humans. XP13512 was not a substrate or inhibitor of major cytochrome P450 isoforms in transfected baculosomes or liver homogenates. The separated isomers of XP13512 showed similar cleavage in human tissues. The prodrug demonstrated active apical to basolateral transport across Caco-2 cell monolayers and pH-dependent passive permeability across artificial membranes. XP13512 inhibited uptake of 14C-lactate by human embryonic kidney cells expressing monocarboxylate transporter type-1, and direct uptake of prodrug by these cells was confirmed using liquid chromatography-tandem mass spectrometry. XP13512 inhibited uptake of 3H-biotin into Chinese hamster ovary cells overexpressing human sodium-dependent multivitamin transporter (SMVT). Specific transport by SMVT was confirmed by oocyte electrophysiology studies and direct uptake studies in human embryonic kidney cells after tetracycline-induced expression of SMVT. XP13512 is therefore a substrate for several high-capacity absorption pathways present throughout the intestine. Therefore, administration of the prodrug should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapentin.Keywords
This publication has 37 references indexed in Scilit:
- XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: II. Improved Oral Bioavailability, Dose Proportionality, and Colonic Absorption Compared with Gabapentin in Rats and MonkeysJournal of Pharmacology and Experimental Therapeutics, 2004
- Molecular Features, Regulation, and Function of Monocarboxylate Transporters: Implications for Drug DeliveryJournal of Pharmaceutical Sciences, 2003
- The absorption of gabapentin following high dose escalationSeizure, 2003
- Treatment of restless legs syndrome with gabapentinNeurology, 2002
- Expression of Large Amino Acid Transporter LAT1 in Rat Brain EndotheliumJournal of Cerebral Blood Flow & Metabolism, 2000
- Effects of Age and Gender on Single‐Dose Pharmacokinetics of GabapentinEpilepsia, 1999
- Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients With Diabetes MellitusA Randomized Controlled TrialJAMA, 1998
- (Acyloxy)alkyl carbamates as novel bioreversible prodrugs for amines: increased permeation through biological membranesJournal of Medicinal Chemistry, 1988
- Biotin absorption from the hindgut of the pig1Journal of Animal Physiology and Animal Nutrition, 1986
- Measurement of rat-intestinal cefuroxime axetil esterase activity: comparison of an h.p.l.c. and coupled-enzyme assayXenobiotica, 1985