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  • Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen.

Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen.

The Journal of pharmacology and experimental therapeutics (2009-06-09)
Ritu Lal, Juthamas Sukbuntherng, Ezra H L Tai, Shubhra Upadhyay, Fenmei Yao, Mark S Warren, Wendy Luo, Lin Bu, Son Nguyen, Jeanelle Zamora, Ge Peng, Tracy Dias, Ying Bao, Maria Ludwikow, Thu Phan, Randall A Scheuerman, Hui Yan, Mark Gao, Quincey Q Wu, Thamil Annamalai, Stephen P Raillard, Kerry Koller, Mark A Gallop, Kenneth C Cundy
RESUMO

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.

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Sigma-Aldrich
Isobutyric acid, 99%
Sigma-Aldrich
Isobutyric acid, puriss. p.a., ≥99.5%
Sigma-Aldrich
Isobutyric acid, ≥99%, FCC, FG
Supelco
Isobutyric acid, analytical standard
Sigma-Aldrich
Isobutyric acid, natural, ≥99%, FCC, FG