Interactions No interactions have been demonstrated in vivo. The manufacturer notes some potential pharmacological interactions with opioids, benzodiazepines, barbiturates, ethanol (alcohol), and other drugs that depress the central nervous system. ACE inhibitors may enhance the adverse/toxic effect of<unk> .<unk>  may enhance the fluid-retaining effect of certain anti-diabetic agents (thiazolidinediones). Pharmacodynamics<unk>  is not a GABAA or GABAB receptor agonist.<unk>  is a gabapentinoid and acts by inhibiting certain calcium channels. Specifically it is a ligand of the auxiliary α2δ subunit site of certain voltage-dependent calcium channels (VDCCs), and thereby acts as an inhibitor of α2δ subunit-containing VDCCs. There are two drug-binding α2δ subunits, α2δ-1 and α2δ-2, and<unk>  shows similar affinity for (and hence lack of selectivity between) these two sites.<unk>  is selective in its binding to the α2δ VDCC subunit. Despite the fact that<unk>  is a GABA analogue, it does not bind to the GABA receptors, does not convert into or another GABA receptor agonist in vivo, and does not directly modulate GABA transport or metabolism. However,<unk>  has been found to produce a dose-dependent increase in the brain expression of L-glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing GABA, and hence may have some indirect GABAergic effects by increasing GABA levels in the brain. There is currently no evidence that the effects of<unk>  are mediated by any mechanism other than inhibition of α2δ-containing VDCCs. In accordance, inhibition of α2δ-1-containing VDCCs by<unk>  appears to be responsible for its anticonvulsant, analgesic, and anxiolytic effects. The endogenous α-amino acids L-leucine and L-isoleucine, which closely resemble<unk>  and the other gabapentinoids in chemical structure, are apparent ligands of the α2δ VDCC subunit with similar affinity as the gabapentinoids (e.g., IC50 = 71 nM for L-isoleucine), and are present in human cerebrospinal fluid at micromolar concentrations (e.g., 12.9 μM for L-leucine, 4.8 μM for L-isoleucine). It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. In accordance, while gabapentinoids like<unk>  and gabapentin have nanomolar affinities for the α2δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids has been said to likely be responsible for this discrepancy.<unk>  was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VDCCs in one study. However, another study found that<unk>  and gabapentin had similar affinities for the human recombinant α2δ-1 subunit (Ki = 32 nM and 40 nM, respectively). In any case,<unk>  is 2 to 4 times more potent than gabapentin as an analgesic and, in animals, appears to be 3 to 10 times more potent than gabapentin as an anticonvulsant. Pharmacokinetics Absorption<unk>  is absorbed from the intestines by an active transport process mediated via the large neutral amino acid transporter 1 (LAT1, SLC7A5), a transporter for amino acids such as L-leucine and L-phenylalanine. Very few (less than 10 drugs) are known to be transported by this transporter. Unlike gabapentin, which is transported solely by the LAT1,<unk>  seems to be transported not only by the LAT1 but also by other carriers. The LAT1 is easily saturable, so the pharmacokinetics of gabapentin are dose-dependent, with diminished bioavailability and delayed peak levels at higher doses. In contrast, this is not the case for<unk> , which shows linear pharmacokinetics and no saturation of absorption. The oral bioavailability of<unk>  is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 900 mg/day). Food does not significantly influence the oral bioavailability of<unk> .<unk>  is rapidly absorbed when administered on an empty stomach, with a Tmax (time to peak levels) of generally less than or equal to 1 hour at doses of 300 mg or less. However, food has been found to substantially delay the absorption of<unk>  and to significantly reduce peak levels without affecting the bioavailability of the drug; Tmax values for<unk>  of 0.6 hours in a fasted state and 3.2 hours in a fed state (5-fold difference), and the Cmax is reduced by 25–31% in a fed versus fasted state. Distribution<unk>  crosses the blood–brain barrier and enters the central nervous system. However, 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.<unk>  has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the volume of distribution of an orally administered dose of<unk>  is approximately 0.56 L/kg.<unk>  is not significantly bound to plasma proteins (<1%). Metabolism<unk>  undergoes little or no metabolism. In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged<unk> . The main metabolite is N-methylpregabalin. Elimination<unk>  is eliminated by the kidneys in the urine, mainly in its unchanged form. It has a relatively short elimination half-life, with a reported value of 6.3 hours. Because of its short elimination half-life,<unk>  is administered 2 to 3 times per day to maintain therapeutic levels. The kidney clearance of<unk>  is 73 mL/minute.
Pregabalin
Imagabalin
Gabapentin
Naproxen
Nabilone
Nortriptyline
Trazodone
Hydrocodone