Arbaclofen Placarbil
Thuốc Gốc
Small Molecule
CAS: 847353-30-4
Cơ Chế Tác Dụng :
Dược Động Học :
Unlike baclofen, absorption of R-baclofen(arbaclofen) is not limited to the upper small intestine. The ability of arbaclofen to be absorbed throughout the gastrointestinal tract allowed for the development of the sustained release formulation, arbaclofen placarbil (AP). In one study of AP absorption in 10 healthy volunteers, one 20mg oral dose of AP, in the presence of food, resulted in a Tmax of 5.05h. The oral bioavailability of R-baclofen in rats when AP was dosed at 10mg/kg was 44 ± 12%, and when dosed at 1mg/kg, oral bioavailability was 68 ± 6%. In monkeys and dogs, the oral bioavailability of R-baclofen when AP was orally dosed was high: 94 ± 16%, and 92 ± 7%, respectively. In comparison, when oral R-balofen was dosed oral bioavailability was 39 ± 21% in monkeys and 49 ± 20% in dogs. Colonic absorption studies measuring R-baclofen bioavailability post intracolonic dosing in rats and monkeys, have revealed low bioavailability with the administration of R-baclofen (7 ± 3% and 3 ± 2%, respectively), and significantly higher R-baclofen bioavailability with intracolonic dosing of AP suspension ( 37 ± 9% and 37 ± 15%, in rats and monkeys respectively). Intracolonic dosing of AP suspension also resulted in high biolavailability of R-baclofen in dogs (77 ± 23%). Absorption throughout the intestine is both passive and active and occurs via the monocarboxylate type 1 transporter.
▧ Volume of Distribution :
Radioactive labeling has shown AP to be widely distributed throughout the body. Tissue distribution occurs mostly to the kidneys and liver.
▧ Metabolism :
In experimental studies using human liver S9 Arbaclofen placarbil was not shown to be a substrate for CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Arbaclofen placarbil, the acyloxyalkyl carbamate prodrug of R-arbaclofen, is believed to undergo hydrolysis by the esterase enzyme human carboxylesterase-2 into the parent amine, R-baclfen. Carbon dioxide, isobutyric acid, isobutyraldehyde, are also expected to be produced in equimolar quantities. The productions of isobutyric acid has been confirmed in vitro untilizing mass spectrometry and gas chromatography.
▧ Route of Elimination :
84-88% renal elimination as R-baclofen. Less than 1% fecal elimination. (2)
▧ Half Life :
IV bolus administration of AP to rats showed that AP was converted to R-baclofen with a half life of 6 minutes.
▧ Clearance :
Blood clearance of an IV bolus of AR in rats resulted in a total blood clearance of 15.81 ± 10.2 L/h/kg in rats. In comparison, blood clearance of an IV bolus of R-baclofen in rats, monkeys, and dogs, resulted in half lives ranging from 1.6-3.4hours, with total blood clearances reported to be 0.51± 0.13L/h/kg in rats, 0.31±0.11L/h/kg in monkeys, and 0.24L±0.01L/h/kg in dogs. (2) In studied utilizing radioactive tracers attached to R-baclofen, 97% of radioactivity was recovered in the urine.
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