Transport of Gabapentin, a γ‐Amino Acid Drug, by System L α‐Amino Acid Transporters: A Comparative Study in Astrocytes, Synaptosomes, and CHO Cells

Abstract

The system L transporter is generally considered to be one of the major Na+‐independent carriers for large neutral α‐amino acids in mammalian cells. However, we found that cultured astrocytes from rat brain cortex accumulate gabapentin, a γ‐amino acid, predominantly by this α‐amino acid transport system. Uptake of gabapentin by system L transporter was also examined in synaptosomes and Chinese hamster ovary (CHO) cells. The inhibition pattern displayed by various amino acids on gabapentin uptake in astrocytes and synaptosomes corresponds closely to that observed for the system L transport activity in CHO cells. Gabapentin and leucine have Km values that equal their Ki values for inhibition of each other, suggesting that leucine and gabapentin compete for the same system L transporter. By contrast, gabapentin exhibited no effect on uptake of GABA, glutamate, and arginine, indicating that these latter three types of brain transporters do not serve for uptake of gabapentin. A comparison of computer modeling analysis of gabapentin and l‐leucine structures shows that although the former is a γ‐amino acid, it can assume a conformation that can resemble the L‐form of a large neutral α‐amino acid such as l‐leucine. The steady‐state kinetic study in astrocytes and CHO cells indicates that the intracellular concentrations of gabapentin are about two to four times higher than that of leucine. The uptake levels of these two substrates are inversely related to their relative exodus rates. The concentrating ability by system L observed in astrocytes is consistent with the substantially high accumulation gradient of gabapentin in the brain tissue as determined by microdialysis.

Spinal Gabapentin and Antinociception: Mechanisms of Action

“…Thus, it could be supposed that spinal GABA receptors may not be directly involved in the antinociceptive effect of intrathecal gabapentin. It has been proposed that gabapentin crosses several membrane barriers in the body via a specific amino acid transporter and competes with leucine, isoleucine, valine, and phenylalanine for transport (1,7). However, intrathecal L-leucine and BCH did not antagonize the antiallodynic effect of intrathecal gabapentin (24).…”

Gabapentin reduces preoperative anxiety and pain catastrophizing in highly anxious patients prior to major surgery: a blinded randomized placebo-controlled trial

“…It is possible that doses lower than 1,200 mg do not reach the therapeutic plasma levels needed to produce clinical anxiolytic effects. 31,32 Furthermore, the documentation of preoperative anxiety prior to enrolment was not undertaken in previous work. 9,10 Biopsychosocial models have suggested that psychological outcomes must be considered in addition to physical outcomes in order to understand pain-related outcomes.…”

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

“…Pregabalin not only binds a 2 d, but is also a substrate for active transport, believed to enter into the CNS by the system L amino-acid transporter (Su et al, 1995(Su et al, , 2005. To improve bioavailability without relying on an active transport mechanism, acid bioisosteres (a substituent or group that imparts similar biological properties to a chemical compound, but enhances the physical properties for drug development) and prodrugs have been employed (Field et al, 2007).…”