RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 315
OP 323
DO 10.1124/jpet.104.067934
VO 311
IS 1
A1 Cundy, Kenneth C.
A1 Branch, Russell
A1 Chernov-Rogan, Tania
A1 Dias, Tracy
A1 Estrada, Toño
A1 Hold, Karin
A1 Koller, Kerry
A1 Liu, Xiaoli
A1 Mann, Adam
A1 Panuwat, Matt
A1 Raillard, Stephen P.
A1 Upadhyay, Shubhra
A1 Wu, Quincey Q.
A1 Xiang, Jia-Ning
A1 Yan, Hui
A1 Zerangue, Noa
A1 Zhou, Cindy X.
A1 Barrett, Ronald W.
A1 Gallop, Mark A.
YR 2004
UL http://jpet.aspetjournals.org/content/311/1/315.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics