Gabapentinoid

Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (i.e., GABA analogues) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor (α2δ subunit), as it is the target of the drugs gabapentin and pregabalin. Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (i.e., GABA analogues) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor (α2δ subunit), as it is the target of the drugs gabapentin and pregabalin. Clinically-used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil. Additionally, phenibut has been found to act as a gabapentinoid in addition to its action of functioning as a GABAB receptor agonist. Further analogues like imagabalin are in clinical trials but have not yet been approved. Other gabapentinoids which are used in scientific research but have not been approved for medical use include atagabalin, 4-methylpregabalin and PD-217,014. Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome. Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal. Evidence finds little benefit and significant risk in those with chronic low back pain. Gabapentinoids are ligands of the auxiliary α2δ subunit site of certain VDCCs, and thereby act as inhibitors of α2δ subunit-containing VDCCs. There are two drug-binding α2δ subunits, α2δ-1 and α2δ-2, and the gabapentinoids show similar affinity for (and hence lack of selectivity between) these two sites. The gabapentinoids are selective in their binding to the α2δ VDCC subunit. However, phenibut uniquely also binds to and acts as an agonist of the GABAB receptor with lower affinity (~5- to 10-fold in one study). Despite the fact that gabapentinoids are GABA analogues, gabapentin and pregabalin do not bind to the GABA receptors, do not convert into GABA or GABA receptor agonists in vivo, and do not modulate GABA transport or metabolism. There is currently no evidence that the relevant actions of gabapentin and pregabalin are mediated by any mechanism other than inhibition of α2δ-containing VDCCs. The endogenous α-amino acids L-leucine and L-isoleucine, which closely resemble the gabapentinoids in chemical structure, are apparent 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). It has been hypothesized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. In accordance, while gabapentin and pregabalin 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. 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, and 6 µM for baclofen. Based on the low affinity of baclofen for the α2δ subunit relative to the GABAB (26-fold difference), its affinity for the α2δ subunit is unlikely to be of pharmacological importance. Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies. Gabapentin and pregabalin are 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, pregabalin 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. Conversely, this is not the case for pregabalin, which shows linear pharmacokinetics and no saturation of absorption. Similarly, gabapentin enacarbil is transported not by the LAT1 but by the monocarboxylate transporter 1 (MCT1) and the sodium-dependent multivitamin transporter (SMVT), and no saturation of bioavailability has been observed with the drug up to a dose of 2,800 mg. Similarly to gabapentin and pregabalin, baclofen, a close analogue of phenibut (specifically being 4-deschlorophenibut), 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. Conversely, the oral bioavailability of pregabalin 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 pregabalin. Conversely, food increases the area-under-curve levels of gabapentin by about 10%. Drugs that increase the transit time of gabapentin in the small intestine can increase its oral bioavailability; when gabapentin was co-administered with oral morphine (which slows intestinal peristalsis), the oral bioavailability of a 600 mg dose of gabapentin increased by 50%. The oral bioavailability of gabapentin enacarbil (as gabapentin) is greater than or equal to 68%, across all doses assessed (up to 2,800 mg), with a mean of approximately 75%. In contrast to the other gabapentinoids, the pharmacokinetics of phenibut have been little-studied, and its oral bioavailability is unknown. 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.