and commercially available
gabapentinoids—
gabapentin,
pregabalin,
phenibut,
baclofen and
mirogabalin.
Pharmacodynamics Gabapentinoids are high affinity
ligands of the
α2δ protein that was first described as an auxiliary subunit of certain voltage-gated calcium channels (
VGCC). Gabapentinoids alter the function of these additional
α2δ binding proteins, and these have been proposed as mediators of drug actions. Conversely, GABA does not bind appreciably to the
α2δ protein. The
endogenous α-amino acids
L-leucine and
L-isoleucine, which resemble the gabapentinoids in
chemical structure (see figure) are ligands of the α2δ VDCC subunit with similar affinity as gabapentin and pregabalin (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). In accordance, while gabapentin and pregabalin have
nanomolar binding affinities for the α2δ subunit, their potencies
in vivo are in the low
micromolar range, and competition for binding by endogenous L-amino acids is likely responsible for this discrepancy. In one study, the affinity (Ki) values of gabapentinoids for the α2δ subunit expressed in rat brain were found to be 0.05 μM for gabapentin, 23 μM for (
R)-phenibut, 39 μM for (
S)-phenibut, and 156 μM for
baclofen. Their affinities (Ki) for the GABAB receptor were >1 mM for gabapentin, 92 μM for (
R)-phenibut, >1 mM for (
S)-phenibut, 6 μM for Baclofen. Pregabalin has demonstrated significantly greater
potency (about 2.5-fold) than gabapentin in clinical studies Very few (less than 10 drugs) are known to be transported by this transporter. Similarly to gabapentin and pregabalin,
baclofen, is transported by the LAT1, although it is a relatively weak
substrate for the transporter. The
oral bioavailability of gabapentin 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. the oral bioavailability of a 600 mg dose of gabapentin increased by 50%. However, it would appear to be at least 63% at a single dose of 250 mg, based on the fact that this fraction of phenibut was recovered from the
urine unchanged in healthy volunteers administered this dose. Conversely, the Tmax of the
extended-release (XR) formulation of gabapentin enacarbil is about 5.1 hours at a single dose of 1,200 mg in a fasted state and 8.4 hours at a single dose of 1,200 mg in a fed state. The LAT1 is highly expressed at the blood–brain barrier and transports the gabapentinoids that bind to it across into the
brain.
Metabolism Gabapentin, pregabalin, and phenibut all undergo little or no
metabolism. Conversely, gabapentin enacarbil is taken twice a day and gabapentin XR (brand name Gralise) is taken once a day. ==Chemistry==