Absorption, Distribution and Excretion
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.
84-88% renal elimination as R-baclofen. Less than 1% fecal elimination. (2)
Radioactive labeling has shown AP to be widely distributed throughout the body. Tissue distribution occurs mostly to the kidneys and liver.
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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Metabolism / Metabolites
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.

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Biological Half-Life
IV bolus administration of AP to rats showed that AP was converted to R-baclofen with a half life of 6 minutes.

: Erickson CA, Veenstra-Vanderweele JM, Melmed RD, McCracken JT, Ginsberg LD, Sikich L, Scahill L, Cherubini M, Zarevics P, Walton-Bowen K, Carpenter RL, Bear MF, Wang PP, King BH. STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J Autism Dev Disord. 2014 Apr;44(4):958-64. doi: 10.1007/s10803-013-1963-z. PubMed PMID: 24272415.

Arbaclofen Placerbil is a prodrug of Arbaclofen, which is a selective gamma-amino-butyric acid type B receptor agonist and the R-enantiomer of baclofen. It was discovered, and has been patented by XenoPort as a new chemical entity with an improved pharmacokinetic profile compared to baclofen, which allows for sustained release properties. Arbaclofen Placerbil was believed to have therapeutic potential in treating gastroesophogeal reflux disease (GERD) and plasticity; however due to discouraging clinical trial results, the drug was abandoned by XenoPort in 2011 for the treatment of GERD. On May 20th, 2013, XenoPort announced plans to terminate the development of Arbaclofen Placerbil for the treatment of multiple sclerosis.

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Drug Indication
Investigated for the treatment of spasticity in multiple sclerosis, acute back spasms, and GERD.

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Mechanism of Action
R-baclofen is postulated to aid in spasticity by acting as an agonist of the inhibitory gamma aminobutyric acid neurotransmission pathway.

C19H26CLNO6

399.8658452034

399.144

847353-30-4

847353-30-4 (Arbaclofen placarbil); 69308-37-8 (Arbaclofen); 63701-55-3 (Arbaclofen hydrochloride)

11281011

Typically exists as solid at room temperature

1.2±0.1 g/cm3

545.1±50.0 °C at 760 mmHg

283.5±30.1 °C

0.0±1.5 mmHg at 25°C

1.523

4.39

2

6

11

27

502

2

CC(C)C(OC(=O)C(C)C)OC(=O)NCC(CC(=O)O)C1=CC=C(C=C1)Cl

JXTAALBWJQJLGN-KSSFIOAISA-N

InChI=1S/C19H26ClNO6/c1-11(2)17(24)26-18(12(3)4)27-19(25)21-10-14(9-16(22)23)13-5-7-15(20)8-6-13/h5-8,11-12,14,18H,9-10H2,1-4H3,(H,21,25)(H,22,23)/t14-,18-/m0/s1

(R)-3-(4-chlorophenyl)-4-((((S)-1-(isobutyryloxy)-2-methylpropoxy)carbonyl)amino)butanoic acid

XP19986 XP-19986 XP 19986 Arbaclofen placarbil.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)