title: XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters.
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-([(alpha-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 (14)C-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 (3)H-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.
authors.affiliation: XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA. kcundy@xenoport.com
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Cundy
authors.forename: Russell
authors.initials: R
authors.lastname: Branch
authors.forename: Tania
authors.initials: T
authors.lastname: Chernov-Rogan
authors.forename: Tracy
authors.initials: T
authors.lastname: Dias
authors.forename: Toño
authors.initials: T
authors.lastname: Estrada
authors.forename: Karin
authors.initials: K
authors.lastname: Hold
authors.forename: Kerry
authors.initials: K
authors.lastname: Koller
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Adam
authors.initials: A
authors.lastname: Mann
authors.forename: Matt
authors.initials: M
authors.lastname: Panuwat
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Raillard
authors.forename: Shubhra
authors.initials: S
authors.lastname: Upadhyay
authors.forename: Quincey Q
authors.initials: QQ
authors.lastname: Wu
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xiang
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.forename: Noa
authors.initials: N
authors.lastname: Zerangue
authors.forename: Cindy X
authors.initials: CX
authors.lastname: Zhou
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Barrett
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gallop
mesh_terms: D000588:Amines / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D018938:Caco-2 Cells; D002219:Carbamates / Q000138:chemical synthesis / Q000378:metabolism*; D006224:Cricetinae; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D005260:Female; D000077206:Gabapentin; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism; D008567:Membranes, Artificial; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D027981:Symporters / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D000588:Amines; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D027283:Large Neutral Amino Acid-Transporter 1; D008567:Membranes, Artificial; D027501:Monocarboxylic Acid Transporters; D011355:Prodrugs; D027981:Symporters; C119981:biotin transporter; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D003577:Cytochrome P-450 Enzyme System