Influence of single nucleotide polymorphism of LAT1 on therapeutic response to gabapentinoids in Pakistani patients with neuropathic pain

Abstract

Gabapentinoids are substrate of L‐type amino acid transporter 1 (LAT1) for distribution across the blood‐brain barrier. The present study aimed to evaluate the effect of LAT1 rs4240803 genetic polymorphism on the clinical efficacy and tolerability of gabapentinoids in Pakistani patients with neuropathic pain. Three‐hundred and ninety‐two patients were recruited, genotyped for SNP rs4240803, and followed up for eight weeks to evaluate the clinical response to gabapentinoids in terms of pain relief, inadequate response, and the emergence of adverse events. LAT1 rs4240803 GG, GA, and AA genotype frequency were 33.42%, 47.96% and 18.62%, respectively. Out of 392 patients, 323 responded to the treatment and 17.6% discontinued either due to insufficient response or intolerable adverse events (AEs). GA genotype was more frequent in non‐responder group (P ˂ 0.001). Maximum pain responders (≥50%) in combination with the lowest incidence of AEs were observed in the GG group, whereas partial responders belonged to GA genotype and with the highest frequency of somnolence (83.6%) and dizziness (69.9%). Overall, 72.5% patients with GA genotype experienced AEs (P ˂ 0.001). In conclusion, clinical outcomes of gabapentinoids are influenced by LAT1 rs4240803 polymorphism and population pharmacogenetics should be considered to evaluate the maximum potential of gabapentinoids in the management of neuropathic pain.

Effect of CYP3A4 and PPARA polymorphism on concentration-to-dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients

“…Genotyping of the relevant polymorphisms may predict the response of the drug and decrease the duration for dose titration thereby reducing the probability of adverse events during dose adjustments. [12][13][14] A genetic polymorphism modifying the structure of the proteins that metabolize drugs may significantly change the pharmacokinetic properties of calcineurin inhibitors eventually causing fluctuations in the time required for dose titration to attain optimum drug levels in the blood. 15 Polymorphism in CYP3A4 and the interrelated PPARA gene have a crucial role in modifying the clinical response of tacrolimus.…”

Lack of impact of OCTN1 gene polymorphisms on clinical outcomes of gabapentinoids in Pakistani patients with neuropathic pain

“…The role of L-type amino acid transporter (LAT1) polymorphism has been suggested in the absorption and distribution of gabapentinoids [26]. Our recent study has reported the significant association of LAT1 rs4240803 variant genotype in the variable clinical efficacy and poor tolerability in Pakistani patients with neuropathic pain [27]. To the best of our knowledge, the present study is the first to report the possible association of OCTN1 L503F and rs3792876 on OCTN1 substrates, gabapentin and pregabalin in the South Asian population.…”