title: XP13512 [(+/-)-1-([(alpha-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 monkeys.
abstract: The absorption of gabapentin (Neurontin) is dose-dependent and variable between patients. Rapid clearance of the drug necessitates dosing three or more times per day to maintain therapeutic levels. These deficiencies appear to result from the low capacity, limited intestinal distribution, and variable expression of the solute transporter responsible for gabapentin absorption. Saturation of this transporter at doses used clinically leads to unpredictable drug exposure and potentially ineffective therapy in some patients. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed by high-capacity nutrient transporters located throughout the intestine. XP13512 was efficiently absorbed and rapidly converted to gabapentin after oral dosing in rats and monkeys. Exposure to gabapentin was proportional to prodrug dose, whereas exposure to intact XP13512 was low. In rats, >95% of an oral dose of (14)C-XP13512 was excreted in urine in 24 h as gabapentin. In monkeys, oral bioavailability of gabapentin from XP13512 capsules was 84.2% compared with 25.4% after a similar oral Neurontin dose. Compared with intracolonic gabapentin, intracolonic XP13512 gave a 17-fold higher gabapentin exposure in rats and 34-fold higher in monkeys. XP13512 may therefore be incorporated into a sustained release formulation to provide extended gabapentin exposure. XP13512 demonstrated improved gabapentin bioavailability, increased dose proportionality, and enhanced colonic absorption. In clinical use, XP13512 may improve the treatment of neuropathic pain, epilepsy, and numerous other conditions by increasing efficacy, reducing interpatient variability, and decreasing frequency of dosing.
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: Thamil
authors.initials: T
authors.lastname: Annamalai
authors.forename: Lin
authors.initials: L
authors.lastname: Bu
authors.forename: Josephine
authors.initials: J
authors.lastname: De Vera
authors.forename: Jenny
authors.initials: J
authors.lastname: Estrela
authors.forename: Wendy
authors.initials: W
authors.lastname: Luo
authors.forename: Payal
authors.initials: P
authors.lastname: Shirsat
authors.forename: Allan
authors.initials: A
authors.lastname: Torneros
authors.forename: Fenmei
authors.initials: F
authors.lastname: Yao
authors.forename: Joan
authors.initials: J
authors.lastname: Zou
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Barrett
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gallop
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002219:Carbamates / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D003106:Colon / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000077206:Gabapentin; D000882:Haplorhini; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D000588:Amines; D002219:Carbamates; D003509:Cyclohexanecarboxylic Acids; D011355:Prodrugs; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin