P/Q type Ca2+ channel

The prodrug (Gabapentin enacarbil/XP13512) demonstrated active apical to basolateral transport across Caco-2 cell monolayers and pH-dependent passive permeability across artificial membranes. XP13512 inhibited uptake of (14)C-lactate by human embryonic kidney cells expressing monocarboxylate transporter type-1, and direct uptake of prodrug by these cells was confirmed using liquid chromatography-tandem mass spectrometry. XP13512 inhibited uptake of (3)H-biotin into Chinese hamster ovary cells overexpressing human sodium-dependent multivitamin transporter (SMVT). Specific transport by SMVT was confirmed by oocyte electrophysiology studies and direct uptake studies in human embryonic kidney cells after tetracycline-induced expression of SMVT. XP13512 is therefore a substrate for several high-capacity absorption pathways present throughout the intestine. Therefore, administration of the prodrug should result in improved gabapentin bioavailability, dose proportionality, and colonic absorption compared with administration of gabapentin.[4]

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The concentration-dependent inhibition of the K+-induced [Ca2+]i increase in synaptosomes (IC50=14 μM; maximal inhibition by 36%) is produced by gabapentin (0-300 μM)[1]. In neocortical slices, gabapentin (100 μM) reduces endogenous aspartate and glutamate's K+-evoked release by 16 and 18%, respectively[1]. In neocortical slices, gabapentin (0-1000 μM) decreases the release of [3H]-noradrenaline evoked by K+ (IC50=48 μM; maximal inhibition of 46%), but not from synaptosomes[1].

Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in the upper small intestine. Saturation of this transporter at doses used clinically leads to dose-dependent pharmacokinetics and high interpatient variability, potentially resulting in suboptimal drug exposure in some patients. Gabapentin enacarbil/XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed throughout the intestine by high-capacity nutrient transporters. XP13512 was stable at physiological pH but rapidly converted to gabapentin in intestinal and liver tissue from rats, dogs, monkeys, and humans. XP13512 was not a substrate or inhibitor of major cytochrome P450 isoforms in transfected baculosomes or liver homogenates. The separated isomers of XP13512 showed similar cleavage in human tissues. [4]

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Gabapentin absorption occurs in only a limited region of the small intestine and saturates at doses used clinically, resulting in dose-dependent pharmacokinetics, high interpatient variability, and potentially ineffective drug exposure. Gabapentin enacarbil/XP13512/GSK1838262 is a novel transported prodrug of gabapentin that is absorbed throughout the entire length of the intestine by high-capacity nutrient transporters. In 4 studies of healthy volunteers (136 subjects total), the pharmacokinetics of XP13512 immediate- and extended-release formulations were compared with those of oral gabapentin. XP13512 immediate-release (up to 2800 mg single dose and 2100 mg twice daily) was well absorbed (>68%, based on urinary recovery of gabapentin), converted rapidly to gabapentin, and provided dose-proportional exposure, whereas absorption of oral gabapentin declined with increasing doses to <27% at 1200 mg. Compared with 600 mg gabapentin, an equimolar XP13512 extended-release dose provided extended gabapentin exposure (time to maximum concentration, 8.4 vs 2.7 hours) and superior bioavailability (74.5% vs 36.6%). XP13512 may therefore provide more predictable gabapentin exposure and decreased dosing frequency. [5]

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The spatial and affective cognitive performance of naive mice in the Morris water maze (MWM), passive avoidance (PA), and modified elevated plus maze (mEPM) tasks is improved by gabapentin (5 and 10 mg/kg; ip; once; male BALB/c mice)[2]. ?In male mice, gabapentin (1–100 mg/kg; intraperitoneally; once) exerts analgesic effect and dose-dependently lowers writhing[3].

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Gabapentin is one of the new antiepileptic drugs (AEDs) launched recently. The advantage of new AEDs includes newer mechanism of action, broad spectrum of antiseizure effects, lesser drug interactions and fewer side effects. Gabapentin (GBP) a GABA analogue, is efficacious in several neurological and psychiatric conditions and it is conventionally used in the treatment of partial epilepsies. In this study, we aimed to evaluate the effects of GBP on learning and memory processes of naive mice in Morris water maze (MWM), passive avoidance (PA) and modified elevated plus maze (mEPM) tests. GBP (5 and 10mg/kg, i.p.) was administered on the probe trial of MWM and on the acquisation session of PA and mEPM tests. In the MWM test, GBP (10mg/kg) significantly increased the time spent in target quadrant and GBP (5 and 10mg/kg) significantly decreased the distance to platform compared to control group. In the mEPM test, GBP (5 and 10mg/kg) significantly decreased the transfer latency compared to control group on the second day and in the PA test, GBP (5 and 10mg/kg) significantly prolonged retention latency compared to control group. Our results indicate that GBP has improving effects on spatial and emotional cognitive performance of naive mice in MWM, PA and mEPM tasks[2].

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Both gabapentin and morphine reduced writhing in a dose-dependent manner. The number of writhes was decreased significantly by gabapentin (50 and 100 mg kg(-1)) and morphine (0.5, 1, 3 and 5 mg kg(-1)) (P < 0.001). Also, the lowest dose of morphine 0.25 mg kg(-1) when combined with low doses of gabapentin significantly decreased the number of writhes (P < 0.005). The combination of a low effective dose of gabapentin (50 mg kg(-1)) with a low dose of morphine decreased the writhing by 94% as compared to the controls. The antinociceptive effect of combined administration was not reversed by naloxone. Conclusion: These data demonstrated the comparable efficacy of gabapentin with morphine in visceral pain. Also, the results showed that the combination of doses of gabapentin and morphine, which were ineffective alone, produced a significant analgesic effect in the writhing model of pain. This may be clinically important in the management of visceral pain[3].

Cytosolic calcium ion concentrations ([Ca(2+)](i)) were measured in rat neocortical synaptosomes using fura-2, and depolarization of synaptosomal membranes was induced by K(+) (30 mM). The release of the endogenous excitatory amino acids glutamate and aspartate was evoked by K(+) (50 mM) and determined by HPLC. The release of [(3)H]-noradrenaline from rat neocortical synaptosomes or slices was evoked by K(+) (15 and 25 mM) and measured by liquid scintillation counting. Gabapentin produced a concentration-dependent inhibition of the K(+)-induced [Ca(2+)](i) increase in synaptosomes (IC(50)=14 microM; maximal inhibition by 36%). The inhibitory effect of gabapentin was abolished in the presence of the P/Q-type Ca(2+) channel blocker omega-agatoxin IVA, but not by the N-type Ca(2+) channel antagonist omega-conotoxin GVIA. Gabapentin (100 microM) decreased the K(+)-evoked release of endogenous aspartate and glutamate in neocortical slices by 16 and 18%, respectively. Gabapentin reduced the K(+)-evoked [(3)H]-noradrenaline release in neocortical slices (IC(50)=48 microM; maximal inhibition of 46%) but not from synaptosomes. In the presence of the AMPA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2, 3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide (NBQX), gabapentin did not reduce [(3)H]-noradrenaline release. Gabapentin did, however, cause inhibition in the presence of the NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849). Gabapentin is concluded to reduce the depolarization-induced [Ca(2+)](i) increase in excitatory amino acid nerve terminals by inhibiting P/Q-type Ca(2+) channels; this decreased Ca(2+) influx subsequently attenuates K(+)-evoked excitatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K(+)-evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradrenaline release [1].

Animal/Disease Models: Male balb/c (Bagg ALBino) mouse ( 35-45 g)[2]
Doses: 5 and 10 mg/kg
Route of Administration: intraperitoneal (ip)injection; once
Experimental Results: Increased the time spent in target quadrant and diminished the distance to platform in MWM test . diminished the transfer latency on second day in mEPM test . Prolonged retention latency in PA test .

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Animal/Disease Models: Male mice (26-30 g)[3]
Doses: 1, 5, 10, 50 and 100 mg/kg
Route of Administration: intraperitoneal (ip)injection; once
Experimental Results: Produced 45-70% inhibition of writhing.

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A total of 96 mice received acetic acid intraperitoneally after administration of saline or gabapentin (1, 5, 10, 50 and 100 mg kg(-1)) or morphine (0.25, 0.5, 1, 3 and 5 mg kg(-1)) or a combination of morphine and gabapentin. Other groups also received naloxone. The number of writhes were counted.[3]

Absorption, Distribution and Excretion
Gabapentin enacarbil is absorbed in the intestines by active transport through the proton-linked monocarboxylate transporter, MCT-1.
Gabapentin enacarbil is eliminated primarily in the urine (94%) and to a lesser extent in the feces (5%).
The volume of distribution is 76L.
Renal clearance of gabapentin is 5 to 7 L/hr.

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Metabolism / Metabolites
Gabapentin enacarbil does not interact with any of the major cytochrome P450 enzymes.

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Biological Half-Life
The elimination half-life of gabapentin is 5.1 to 6.0 hours.

Protein Binding
Gabapentin plasma protein binding is less than 3%.

[1]. Inhibition of neuronal Ca(2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices. Br J Pharmacol. 2000 Jun;130(4):900-6.

[2]. Gabapentin, A GABA analogue, enhances cognitive performance in mice. Neurosci Lett. 2011 Apr 1;492(2):124-8.

[3]. Gabapentin action and interaction on the antinociceptive effect of morphine on visceral pain in mice. Eur J Anaesthesiol. 2008 Feb;25(2):129-34.

[4]. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004 Oct;311(1):315-23.

[5]. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol. 2008 Dec;48(12):1378-88.

Pharmacodynamics
Since gabapentin enacarbil is a prodrug of gabapentin, it's physiological effects are the same as gabapentin. Concerning PHN, gabapentin prevents allodynia and hyperalgesia.

C16H27NO6

329.39

329.183

C, 58.34; H, 8.26; N, 4.25; O, 29.14

478296-72-9

Gabapentin;60142-96-3; Gabapentin enacarbil;478296-72-9;Gabapentin hydrochloride;60142-95-2;Gabapentin-d4;1185039-20-6

9883933

Light yellow to brown ointment

1.1±0.1 g/cm3

482.0±20.0 °C at 760 mmHg

65ºC

245.3±21.8 °C

0.0±2.6 mmHg at 25°C

1.481

3.07

2

6

9

23

428

0

O=C(O)CC1(CNC(OC(OC(C(C)C)=O)C)=O)CCCCC1

TZDUHAJSIBHXDL-UHFFFAOYSA-N

InChI=1S/C16H27NO6/c1-11(2)14(20)22-12(3)23-15(21)17-10-16(9-13(18)19)7-5-4-6-8-16/h11-12H,4-10H2,1-3H3,(H,17,21)(H,18,19)

(1-{[({(1RS)-1-[isobutyryloxy]ethoxy}carbonyl) amino]methyl}cyclohexyl)acetic acid

XP-13512; XP 13512; Gabapentin enacarbil; 478296-72-9; Solzira; XP13512; Horizant; Regnite

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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

DMSO : ≥ 100 mg/mL (~303.59 mM)
Ethanol : ~100 mg/mL (~303.59 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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