Interactive

No interaction has been demonstrated in vivo. Manufacturers note potential pharmacological interactions with opioids, benzodiazepines, barbiturates, ethanol (alcohol), and other drugs that inhibit the central nervous system. ACE inhibitors may enhance the adverse/toxic effects of pregabalin. Pregabalin may enhance the retention effect of some antidiabetic drugs (thiazolidinedione).

Pharmacodynamics

Pregabalin, a gabapentin, works by inhibiting certain calcium channels. Specifically, it is a ligand at the helper α2δ subunit site of certain voltage-dependent calcium channels (VDCCs) and therefore acts as an inhibitor of VDCCs containing α2δ subunits. There are two drug-bound α2δ subunits, α2δ-1 and α2δ-2, for which pregabalin shows similar affinity (and therefore lack selectivity). Pregabalin is selective in its binding to the α2δ VDCC subunit. Although pregabalin is a GABA analogue, it does not bind to GABA receptors, is not converted into GABA or another GABA receptor agonist in the body, and does not directly regulate GABA transport or metabolism. However, pregabalin has been found to produce a dose-dependent increase in the expression of L-glutamic acid decarboxylase (GAD) in the brain, which is responsible for the synthesis of GABA, and therefore may produce some indirect GABaergic effects by increasing GABA levels in the brain. There is no evidence that the effect of pregabalin is mediated by any mechanism other than inhibition of α2δ -containing VDCC. Correspondingly, pregabalin's inhibition of α2δ-1 containing VDCC seems to be responsible for its anticonvulsive, analgesic and antianxiety effects.

The endogenous α -amino acids L-leucine and L-isoleucine are chemically similar to pregabalin and other gabapentines, are obvious ligands of the α2δ VDCC subunit, and have similar affinity with gabapentines (for example, l-IC50 = 71 nM isoleucine). It is also present in human cerebrospinal fluid at micromolar concentrations (e.g., l-leucine at 12.9 μM and L-isoleucine at 4.8 μM). In theory, they may be endogenous ligands of subunits, and they may competitively antagonize gabapentin. Thus, although gabapentin drugs such as pregabalin and gabapentin have nanomolar affinity for the α2δ subunit, their potency in vivo is in the low micromole range, and it is suggested that competition for binding of endogenous L-amino acids may account for this difference.

Pregabalin was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VDCCs in one study. However, another study found that pregabalin and gabapentin had similar affinities for the human recombinant α2δ-1 subunit (Ki = 32 nM and 40 nM, respectively). In any case, pregabalin 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.