Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen.
Baclofen is a racemic GABA(B) receptor agonist that has a number of significant pharmacokinetic limitations, including a narrow window of absorption in the upper small intestine and rapid clearance from the blood. Arbaclofen placarbil is a novel transported prodrug of the pharmacologically active R-isomer of baclofen designed to be absorbed throughout the intestine by both passive and active mechanisms via the monocarboxylate type 1 transporter. Arbaclofen placarbil is rapidly converted to R-baclofen in human and animal tissues in vitro. This conversion seems to be primarily catalyzed in human tissues by human carboxylesterase-2, a major carboxylesterase expressed at high levels in various tissues including human intestinal cells. Arbaclofen placarbil was efficiently absorbed and rapidly converted to R-baclofen after oral dosing in rats, dogs, and monkeys. Exposure to R-baclofen was proportional to arbaclofen placarbil dose, whereas exposure to intact prodrug was low. Arbaclofen placarbil demonstrated enhanced colonic absorption, i.e., 5-fold higher R-baclofen exposure in rats and 12-fold higher in monkeys compared with intracolonic administration of R-baclofen. Sustained release formulations of arbaclofen placarbil demonstrated sustained R-baclofen exposure in dogs with bioavailability up to 68%. In clinical use, arbaclofen placarbil may improve the treatment of patients with gastroesophageal reflux disease, spasticity, and numerous other conditions by prolonging exposure and decreasing the fluctuations in plasma levels of R-baclofen.
Lal
Ritu
R
XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA. ritu.lal@xenoport.com
Sukbuntherng
Juthamas
J
Tai
Ezra H L
EH
Upadhyay
Shubhra
S
Yao
Fenmei
F
Warren
Mark S
MS
Luo
Wendy
W
Bu
Lin
L
Nguyen
Son
S
Zamora
Jeanelle
J
Peng
Ge
G
Dias
Tracy
T
Bao
Ying
Y
Ludwikow
Maria
M
Phan
Thu
T
Scheuerman
Randall A
RA
Yan
Hui
H
Gao
Mark
M
Wu
Quincey Q
QQ
Annamalai
Thamil
T
Raillard
Stephen P
SP
Koller
Kerry
K
Gallop
Mark A
MA
Cundy
Kenneth C
KC
D000818:Animals; D001418:Baclofen / Q000493:pharmacokinetics* / Q000031:analogs & derivatives; D001667:Binding, Competitive / Q000187:drug effects; D002087:Butyrates / Q000378:metabolism; D043182:Carboxylesterase / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018755:GABA Agonists / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption; D058610:Isobutyrates; D007527:Isoenzymes / Q000187:drug effects; D018374:LLC-PK1 Cells; D008297:Male; D008567:Membranes, Artificial; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014920:Wine
D002087:Butyrates; D018755:GABA Agonists; D058610:Isobutyrates; D007527:Isoenzymes; D008567:Membranes, Artificial; D011355:Prodrugs; C020380:isobutyric acid; D003577:Cytochrome P-450 Enzyme System; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase; D001418:Baclofen; C543531:arbaclofen placarbil