RT Journal Article
SR Electronic
T1 Arbaclofen Placarbil, a Novel <em>R</em>-Baclofen Prodrug: Improved Absorption, Distribution, Metabolism, and Elimination Properties Compared with <em>R</em>-Baclofen
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 911
OP 921
DO 10.1124/jpet.108.149773
VO 330
IS 3
A1 Ritu Lal
A1 Juthamas Sukbuntherng
A1 Ezra H. L. Tai
A1 Shubhra Upadhyay
A1 Fenmei Yao
A1 Mark S. Warren
A1 Wendy Luo
A1 Lin Bu
A1 Son Nguyen
A1 Jeanelle Zamora
A1 Ge Peng
A1 Tracy Dias
A1 Ying Bao
A1 Maria Ludwikow
A1 Thu Phan
A1 Randall A. Scheuerman
A1 Hui Yan
A1 Mark Gao
A1 Quincey Q. Wu
A1 Thamil Annamalai
A1 Stephen P. Raillard
A1 Kerry Koller
A1 Mark A. Gallop
A1 Kenneth C. Cundy
YR 2009
UL http://jpet.aspetjournals.org/content/330/3/911.abstract
AB Baclofen is a racemic GABAB 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. The American Society for Pharmacology and Experimental Therapeutics