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 monkeys

Journal of Pharmacology and Experimental Therapeutics

Volumn 311, Issue 1, 2004, Pages 324-333

  Cundy, Kenneth C ^a   Annamalai, Thamil ^a   Bu, Lin ^a   De Vera, Josephine ^a   Estrela, Jenny ^a   Luo, Wendy ^a   Shirsat, Payai ^a   Torneros, Allan ^a   Yao, Fenmei ^a   Zou, Joan ^a   Barrett, Ronald W ^a   Gallop, Mark A ^a  

^a XenoPort Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [[(ALPHA ISOBUTANOYLOXYETHOXY)CARBONYL]AMINOMETHYL] 1 CYCLOHEXANE ACETIC ACID; ACETIC ACID DERIVATIVE; GABAPENTIN; PRODRUG; UNCLASSIFIED DRUG; XP 13512; 1 (((ALPHA ISOBUTANOYLOXYETHOXY)CARBONYL)AMINOMETHYL) 1 CYCLOHEXANEACETIC ACID; 1-(((ALPHA-ISOBUTANOYLOXYETHOXY)CARBONYL)AMINOMETHYL)-1-CYCLOHEXANEACETIC ACID; 4 AMINOBUTYRIC ACID; AMINE; CARBAMIC ACID DERIVATIVE; CYCLOHEXANECARBOXYLIC ACID DERIVATIVE; DRUG DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CEREBROSPINAL FLUID ANALYSIS; COLON ABSORPTION; CONTROLLED STUDY; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG EXCRETION; DRUG HALF LIFE; DRUG STRUCTURE; DRUG TRANSPORT; DRUG UPTAKE; DRUG URINE LEVEL; EPILEPSY; MALE; MONKEY; NEUROPATHIC PAIN; NONHUMAN; PRIORITY JOURNAL; RAT; SPECIES DIFFERENCE; SUSTAINED RELEASE PREPARATION; ANIMAL; BIOAVAILABILITY; CEREBROSPINAL FLUID; COLON; HAPLORHINI; INTESTINE ABSORPTION; INTRAVENOUS DRUG ADMINISTRATION; METABOLISM; ORAL DRUG ADMINISTRATION; PHYSIOLOGY; SPRAGUE DAWLEY RAT; TISSUE DISTRIBUTION;

ADMINISTRATION, ORAL; AMINES; ANIMALS; BIOLOGICAL AVAILABILITY; CARBAMATES; COLON; CYCLOHEXANECARBOXYLIC ACIDS; GAMMA-AMINOBUTYRIC ACID; HAPLORHINI; INJECTIONS, INTRAVENOUS; INTESTINAL ABSORPTION; PRODRUGS; RATS; RATS, SPRAGUE-DAWLEY; SPECIES SPECIFICITY; TISSUE DISTRIBUTION;

EID: 4644251930     PISSN: 00223565     EISSN: None     Source Type: Journal    
DOI: 10.1124/jpet.104.067959     Document Type: Article

References (34)

1. 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.
2. Ben-Menachem E, Persson LI, and Hedner T (1992) Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin. Epilepsy Res 11:45-49.
3. Ben-Menachem E, Soderfelt B, Hamberger A, Hedner T, and Persson LI (1995) Seizure frequency and CSF parameters in a double-blind placebo controlled trial of gabapentin in patients with intractable complex partial seizures. Epilepsy Res 21:231-236.
4. Berry DJ, Beran RG, Plunkett MJ, Clarke LA, and Hung WT (2003) The absorption of gabapentin following high dose escalation. Seizure 12:28-36.
5. Birkebaek NH, Memmert K, Mortensen J, Dirksen H, and Christensen MF (1990) Fractional gastrointestinal transit time: intra- and interindividual variation. Nucl Med Commun 11:247-252.
6. 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.
7. Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, Koller K, Liu X, Mann A, Panuwat M, et al. (2004) XP13512, a novel gabapentin prodrug: I. design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther 311:315-323.
8. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, and Hernandez G (2002) Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 59:1573-1579.
9. Gee NS, Brown JP, Diesanayake VU, Offord J, Thurlow R, and Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 271:5768-5776.
10. 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.
11. Gidal BE, Radulovic LL, Kruger S, Rutecki P, Pitterle M, and Bockbrader HN (2000) Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability. Epilepsy Res 40:123-127.
12. Gleiter CH and Morike KE (2002) Clinical pharmacokinetics of candesartan. Clin Pharmacokinet 41:7-17.
13. 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.
14. Juel C and Halestrap AP (1999) Lactate transport in skeletal muscle: role and regulation of the monocarboxylate transporter. J Physiol 517:633-642.
15. Kelly KM (1998) Gabapentin: antiepileptic mechanism of action. Neuropsychobiology 38:139-144.
16. Kriel RL, Birnbaum AK, Cloyd JC, Ricker BJ, Jones Saete C, and Caruso KJ (1997) Failure of absorption of gabapentin after rectal administration. Epilepsia 38:1242-1244.
17. Luer MS, Hamani C, Dujovny M, Gidal B, Cwik M, Deyo K, and Fischer JH (1999) Saturable transport of gabapentin at the blood-brain barrier. Neurol Res 21:559-562.
18. Marais E, Klugbauer N, and Hofmann F (2001) Calcium channel alpha(2)delta subunits-structure and gabapentin binding. Mol Pharmacol 59:1243-1248.
19. McLean MJ (1995) Gabapentin. Epilepsia 36 (Suppl 2):S73-S86.
20. McLean MJ (1999) Gabapentin in the management of convulsive disorders. Epilepsia 40 (Suppl 6):S39-S50.
21. Pollack MH, Matthews J, and Scott EL (1998) Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry 155:992-993.
22. Prasad PD, Wang H, Huang W, Kekuda R, Rajan DP, Leibach FH, and Ganapathy V (1999) Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. Biochem Biophys Res Commun 16:283-288.
23. 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.
24. Rice AS and Maton S (2001) Postherpetic Neuralgia Study Group: gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain 94:215-224.
25. Richter A, Anton SE, Koch P, and Dennett SL (2003) The impact of reducing dose frequency on health outcomes. Clin Ther 25:2307-2335.
26. Riley SA, Sutcliffe F, Kim M, Kapas M, Rowland M, and Turnberg LA (1992) The influence of gastrointestinal transit on drug absorption in healthy volunteers. Br J Clin Pharmacol 34:32-39.
27. 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.
28. 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.
29. Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, and Klassen CD (2002) Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos 30:212-219.
30. Stevenson CM, Kim J, and Fleisher D (1997) Colonic absorption of antiepileptic agents. Epilepsia 38:63-67.
31. 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.
32. 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.
33. Vollmer KO, von Hodenberg A, and Kolle EU (1986) Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneim-Forsch 36:830-839.
34. +-dependent multivitamin transporter: cloning, functional expression, gene structure and chromosomal localization. J Biol Chem 274:14875-14883.