Pharmacodynamics<unk>  is a ligand of the α2δ calcium channel subunit. α2δ is an auxiliary protein connected to the main α1 subunit (the channel-forming protein) of high voltage activated voltage-dependent calcium channels (L-type, N-type, P/Q type, and R-type).<unk>  is not a direct channel blocker: it exerts its actions by disrupting the regulatory function of α2δ and its interactions with other proteins.<unk>  prevents delivery of the calcium channels to the cell membrane, reduces the activation of the channels by the α2δ subunit, decreases signaling leading to neurotransmitters release, and disrupts interactions of α2δ with NMDA receptors, neurexins, and thrombospondins. Out of the four known isoforms of α2δ protein,<unk>  binds with similar high affinity to two: α2δ-1 and α2δ-2. Most of the pharmacological properties of<unk>  are explained by its binding to just one isoform - α2δ-1. The endogenous α-amino acids L-leucine and L-isoleucine, which resemble<unk>  in chemical structure, bind α2δ with similar affinity to<unk>  and are present in human cerebrospinal fluid at micromolar concentrations. They may be the endogenous ligands of the α2δ subunit, and they competitively antagonize the effects of<unk> . Accordingly, while<unk>  has nanomolar affinity for the α2δ subunit, its potency in vivo is in the low micromolar range, and competition for binding by endogenous L-amino acids is likely to be responsible for this discrepancy.<unk>  is a potent activator of voltage-gated potassium channels KCNQ3 and KCNQ5, even at low nanomolar concentrations. However, this activation is unlikely to be the dominant mechanism of<unk> 's therapeutic effects. Despite the fact that<unk>  is a structural GABA analogue, and in spite of its name, it does not bind to the GABA receptors, does not convert into or another GABA receptor agonist in vivo, and does not modulate GABA transport or metabolism. Pharmacokinetics<unk>  is absorbed from the intestines by an active transport process mediated via an amino acid transporter, presumably, LAT2. As a result, the pharmacokinetics of<unk>  is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses. The oral bioavailability of<unk>  is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule. Drugs that increase the transit time of<unk>  in the small intestine can increase its oral bioavailability; when<unk>  was co-administered with oral morphine, the oral bioavailability of a 600 mg dose of<unk>  increased by 50%.<unk>  at a low dose of 100 mg has a Tmax (time to peak levels) of approximately 1.7 hours, while the Tmax increases to 3 to 4 hours at higher doses. Food does not significantly affect the Tmax of<unk>  and increases the Cmax and area-under-curve levels of<unk>  by approximately 10%.<unk>  can cross the blood–brain barrier and enter the central nervous system.<unk>  concentration in cerebrospinal fluid is approximately 9-14% of its blood plasma concentration. Due to its low lipophilicity,<unk>  requires active transport across the blood–brain barrier. The LAT1 is highly expressed at the blood–brain barrier and transports<unk>  across into the brain. As with intestinal absorption mediated by an amino acid transporter, the transport of<unk>  across the blood–brain barrier by LAT1 is saturable.<unk>  does not bind to other drug transporters such as P-glycoprotein (ABCB1) or OCTN2 (SLC22A5). It is not significantly bound to plasma proteins (<1%).<unk>  undergoes little or no metabolism.<unk>  is eliminated renally in the urine. It has a relatively short elimination half-life, with the reported average value of 5 to 7 hours. This value changes with increasing doses, from 5.4 hours for a 200 mg single dose, to 8.3 hours for a 1,400 mg dose. Because of its short elimination half-life,<unk>  must be administered 3 to 4 times per day to maintain therapeutic levels.<unk>  XR (brand name Gralise) is taken once a day.
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