XP13512: Synthesis, in Vitro Metabolism, and Transport
323
Halestrap AP and Price NT (1999) The proton-linked monocarboxylate transporter
least two high-capacity solute transporters (MCT-1 and
SMVT) that are expressed along the length of the intestine.
In addition, XP13512 displays pH-dependent passive perme-
ability. Therefore, the in vivo absorption of XP13512 is likely
to be mediated by a combination of passive absorption and
active transport. This would be expected to lead to efficient
oral bioavailability without the limitation of saturation ob-
served with oral gabapentin. As a result, oral dosing of
XP13512 should provide greater dose proportionality and
hence more predictable gabapentin exposure than currently
provided by oral gabapentin. Furthermore, the broad intes-
tinal distribution of MCT-1 and SMVT should facilitate co-
lonic absorption of XP13512, raising the possibility that the
prodrug may be successfully incorporated into a controlled
release formulation. Such a formulation may deliver a sus-
tained level of gabapentin in plasma, allowing a decreased
frequency of dosing, improved patient compliance, and ulti-
mately superior therapy. The effects of the superior transport
properties of XP13512 on the resulting oral bioavailability,
dose proportionality, colonic absorption, and tissue distribu-
tion of gabapentin in rats and monkeys are described in a
companion paper (Cundy et al., 2004).
(MCT) familiy: structure, function and regulation. Biochem J 343:281–299.
Kriel RL, Birnbaum AK, Cloyd JC, Ricker BJ, Jones Saete C, and Caruso KJ (1997)
Failure of absorption of gabapentin after rectal administration. Epilepsia 38:1242–
1
244.
Lagr e` ze WA, Muller-Velten R, and Feuerstein TJ (2001) The neuroprotective prop-
erties of gabapentin-lactam. Graefes Arch Clin Exp Ophthalmol 239:845–849.
Matsuo H, Tsukada S, Nakata T, Chairoungdua A, Kim DK, Cha SH, Inatomi J,
Yorifuji H, Fukuda J, Endou H, et al. (2000) Expression of a system L neutral
amino acid transporter at the blood-brain barrier. Neuroreport 11:3507–3511.
McLean MJ (1999) Gabapentin in the management of convulsive disorders. Epilepsia
40 (Suppl 6):S39–S50.
McLean MJ (1995) Gabapentin. Epilepsia 36 (Suppl 2):S73–S86.
Pollack MH, Matthews J, and Scott EL (1998) Gabapentin as a potential treatment
for anxiety disorders. Am J Psychiatry 155:992–993.
Potschka H, Feuerstein TJ, and Loscher W (2000) Gabapentin-lactam, a close ana-
logue of the anticonvulsant gabapentin, exerts convulsant activity in amygdala
kindled rats. Naunyn Schmiedebergs Arch Pharmacol 361:200–205.
Prasad PD, Wang H, Huang W, Fei YJ, Leibach FH, Devoe LD, and Ganapathy V
ϩ
(1999a) Molecular and functional characterization of the intestinal Na
-
dependent multivitamin transporter. Arch Biochem Biophys 366:95–106.
Prasad PD, Wang H, Huang W, Kekuda R, Rajan DP, Leibach FH, and Ganapathy
V (1999b) Human LAT1, a subunit of system L amino acid transporter: molecular
cloning and transport function. Biochem Biophys Res Commun 16:283–288.
Radulovic L, Turck D, Von Hodenberg A, Vollmer K, McNally W, Dehart P, Hanson
B, Bockbrader H, and Chang T (1995) Disposition of gabapentin (Neurontin) in
mice, rats, dogs and monkeys. Drug Metab Dispos 23:441–448.
Reynolds RC (1998) Metabolism and pharmacokinetics of sucrose acetate isobutyrate
(
SAIB) and sucrose octa-isobutyrate (SOIB) in rats, dogs, monkeys or humans: a
review. Food Chem Toxicol 36:95–99.
Rice AS and Maton S; Postherpetic Neuralgia Study Group (2001) Gabapentin in
postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain
94:215–224.
Acknowledgments
Richter A, Anton SE, Koch P, and Dennett SL (2003) The impact of reducing dose
frequency on health outcomes. Clin Ther 25:2307–2335.
Rowbotham M, Harden N, Stacey B, Bernstein P, and Magnus-Miller L (1998)
Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled
trial. J Am Med Assoc 280:1837–1842.
Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, and Rubin S (1998) Biotin uptake
by human colonic epithelial NCM460 cells: a carrier-mediated process shared with
pantothenic acid. Am J Physiol 275:C1365–C1371.
Sekine T, Kusuhara H, Utsunomiya-Tate N, Tsuda M, Sugiyama Y, Kanai Y, and
Endou H (1998) Molecular cloning and characterization of high-affinity carnitine
transporter from rat intestine. Biochem Biophys Res Commun 251:586–591.
Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, and Klaassen CD (2002) Tissue
distribution and renal developmental changes in rat organic cation transporter
mRNA levels. Drug Metab Dispos 30:212–219.
Sorrell MF, Frank O, Thomson AD, Aquino A, and Baker H (1971) Absorption of
vitamins from the large intestine. Nutr Res Int 3:143–148.
Stein J, Zores M, and Schroder O (2000) Short-chain fatty acid (SCFA) uptake into
Caco-2 cells by a pH-dependent and carrier mediated transport mechanism. Eur J
Nutr 39:121–125.
Stewart BH, Chan OH, Lu RH, Reyner EL, Schmid HL, Hamilton HW, Steinbaugh
BA, and Taylor MD (1995) Comparison of intestinal permeabilities determined in
multiple in vitro and in situ models: relationship to absorption in humans. Pharm
Res (NY) 12:693–699.
Stewart BH, Kugler AR, Thompson PR, and Bockbrader HN (1993) A saturable
transport mechanism in the intestinal absorption of gabapentin is the underlying
cause of the lack of proportionality between increasing dose and drug levels in
plasma. Pharm Res (NY) 10:276–281.
We thank Laxminarayan Bhat, Manisha Kotecha, Yunxiao Li,
Madhu Menaka, Khan Pham, Emily Tate, Katie Woodford, and
Fenmei Yao (XenoPort, Inc.) for additional contributions.
References
Alexander J, Cargill R, Michelson SR, and Schwam H (1988) (Acyloxy)alkyl carbam-
ates as novel bioreversible prodrugs for amines: increased permeation through
biological membranes. J Med Chem 31:318–322.
Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux
L, and Garofalo E (1998) Gabapentin for the symptomatic treatment of painful
neuropathy in patients with diabetes mellitus: a randomized controlled trial. J Am
Med Assoc 280:1831–1836.
Barth CA, Rigg M, and Hagenmeister H (1986) Biotin absorption from the hind-gut
of the pig. J Anim Physiol Anim Nutr 55:128–134.
Berry DJ, Beran RG, Plunkett MJ, Clarke LA, and Hung WT (2003) The absorption
of gabapentin following high dose escalation. Seizure 12:28–36.
Boyd RA, Turck D, Abel RB, Sedman AJ, and Bockbrader HN (1999) Effects of age
and gender on single-dose pharmacokinetics of gabapentin. Epilepsia 40:474–479.
Campbell CJ and Langley C (1985) Measurement of rat-intestinal cefuroxime axetil
esterase activity: comparison of an HPLC and coupled-enzyme assay. Xenobiotica
15:1011–1019.
Cundy KC, Annamalai T, Bu L, De Vera J, Estrela J, Luo W, Shirsat P, Torneros A,
Yao F, Zou J, et al. (2004) XP13512 [(Ϯ)-1-([(␣-isobutanoyloxyethoxy)carbon-
yl]aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. im-
proved oral bioavailability, dose proportionality, and colonic absorption compared
with gabapentin in rats and monkeys. J Pharmacol Exp Ther 311:324–333.
Duelli R, Enerson BE, Gerhart DZ, and Drewes LR (2000) Expression of large amino
acid transporter LAT1 in rat brain endothelium. J Cereb Blood Flow Metab
Sugano K, Hamada H, Machida M, Ushio H, Saitoh K, and Terada K (2001) Opti-
mized conditions of bio-mimetic artificial membrane permeation assay. Int
J Pharm 228:181–188.
Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Shimane M, Sai Y, and Tsuji A
20:1557–1562.
(1998) Molecular and functional identification of sodium ion-dependent, high af-
Enerson BE and Drewes LR (2003) Molecular features, regulation and function of
finity human carnitine transporter OCTN2. J Biol Chem 273:20378–20382.
Tosco M, Orsenigo MN, Gastaldi G, and Faelli A (2000) An endogenous monocar-
boxylate transport in Xenopus laevis oocytes. Am J Physiol Regul Integr Comp
Physiol 278:R1190–5.
monocarboxylate transporters: implications for drug delivery. J Pharm Sci 92:
1531–1544.
Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, and Her-
nandez G (2002) Treatment of restless legs syndrome with gabapentin: a double-
blind, cross-over study. Neurology 59:1573–1579.
Uchino H, Kanai Y, Kim do K, Wempe MF, Chairoungdua A, Morimoto E, Anders
MW, and Endou H (2002) Transport of amino acid-related compounds mediated by
L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate
recognition. Mol Pharmacol 61:729–737.
Gidal BE, DeCerce J, Bockbrader HN, Gonzalez J, Kruger S, Pitterle ME, Rutecki P,
and Ramsay RE (1998) Gabapentin bioavailability: effect of dose and frequency of
administration in adult patients with epilepsy. Epilepsy Res 31:91–99.
Gidal BE, Radulovic LL, Kruger S, Rutecki P, Pitterle M, and Bockbrader HN (2000)
Inter- and intra-subject variability in gabapentin absorption and absolute bio-
availability. Epilepsy Res 40:123–127.
Wang H, Huang W, Fei YJ, Xia H, Yang-Feng TL, Leibach FH, Devoe LD, Ganapa-
ϩ
thy V, and Prasad PD (1999) Human placental Na -dependent multivitamin
transporter: cloning, functional expression, gene structure and chromosomal lo-
calization. J Biol Chem 274:14875–14883.
Gleiter CH and Morike KE (2002) Clinical pharmacokinetics of candesartan. Clin
Pharmacokinet 41:7–17.
Guttuso T Jr, Kurlan R, McDermott MP, and Kieburtz K (2003) Gabapentin’s effects
on hot flashes in postmenopausal women: a randomized controlled trial. Obstet
Gynecol 101:337–345.
Address correspondence to: Dr. Kenneth C. Cundy, XenoPort, Inc., 3410 Central
Expressway, Santa Clara, CA 95051. E-mail: kcundy@xenoport.com