Research Article Role of Taurine Transporter in the Retinal Uptake of Vigabatrin Anitha Police, 1 Vijay Kumar Shankar, 1 and S. Narasimha Murthy 1,2 Received 22 March 2020; accepted 20 June 2020 Abstract. Vigabatrin (VGB) is a first-line drug used for treatment of infantile spasms. On therapeutic dose, VGB accumulates in the retina causing permanent peripheral visual field constriction. The mechanism involved in retinal accumulation of VGB is ambiguous. In the present study, mechanism of VGB transport into retina was evaluated. VGB uptake into retina was studied in vitro using human adult retinal pigment epithelial (ARPE-19) cells as a model for outer blood retinal barrier. The VGB cell uptake studies demonstrated saturation kinetics with K m value of 13.1 mM and uptake was significantly increased at pH 7.4 and hyperosmolar conditions indicating involvement of carrier-mediated Na + –Cl - -dependent transporter. In the presence of taurine transporter (TauT) substrates (taurine and GABA) and inhibitor guanidinoethyl sulfonate (GES), the uptake of VGB decreased significantly demonstrating contribution of TauT. The VGB retinal levels in rats were decreased by 1.5- and 1.3-folds on chronic administration of GES and taurine, respectively. In conclusion, this study demonstrated the TauT involvement in VGB uptake and accumulation in retina. KEY WORDS: active transport; blood-retinal barrier; solute carrier (SLC) transporter(s). INTRODUCTION Vigabatrin (VGB) is an anti-epileptic drug of choice for treatment of infantile spasms associated with tuberous sclerosis complex (1). In treatment of other complex partial seizures, VGB is used as an adjunct therapy (2) VGB is a γ- vinyl-aminobutyric acid, structural analog of inhibitory neu- rotransmitter γ-aminobutyric acid (GABA). VGB elicits therapeutic activity by suicidal inhibition of GABA- transaminase thereby preventing degradation of GABA and thus increasing their levels at the synaptic cleft of neurons (1). VGB is a low molecular weight, hydrophilic compound with 60–70% of oral bioavailability and only 10% of absorbed VGB crosses the blood brain barrier (3). On chronic administration of VGB, adults and infants were diagnosed with peripheral atrophy of retinal nerve fiber layer and decreased electroretinogram amplitudes indicating damage to the retina (4). Retinal damage causes adverse secondary events leading to bilateral concentric constriction of the visual field and abnormal visual acuity in 30–40% of patients (4,5). Baseline visual field testing or electroretinography should be conducted before initiation of treatment and regularly thereafter to monitor the functions of retina. VGB is approved by the USFDA with black box warning for potential benefit, which outweigh the risk of causing permanent concentric visual field defects (6). Preclinical studies of VGB chronic administration have demonstrated that ocular toxicity is caused by VGB accumulation in the retina (7,8). Accumulated VGB increases GABA concentra- tions significantly higher in the retina compared with the brain (7,9), and studies have reported VGB treatment in rodent models decreases taurine levels in the retina (9–11). The preclinical studies demonstrated taurine supplementation decreases ocular toxicity on VGB administration (11–13). Taurine is an antioxidant which plays a major role in neuroprotective activities and taurine deficiency causes reti- nal degeneration (14,15). The mechanism involved in retinal accumulation of VGB and retinal taurine depletion on VGB chronic administration is ambiguous. The uptake of the drug from circulating blood to ocular tissues is via blood aqueous barrier and the blood retinal barrier (BRB). At retinal barrier, lipophilic drugs are transported through ABC transporters, and amino acid mimetic drugs via solute carrier nutrient transporters (16). In vitro (CaCo2 and MDCK) and in vivo rat studies have demonstrated VGB is majorly transported by proton-coupled amino acid transporter-1 (PAT1/SLC36A1) across the intes- tinal barrier (17–19) Reported studies have shown PAT1 is involved in cellular influx of zwitterionic amino acids (glycine, proline, and alanine), drugs (D-serine, betaine, and D- cycloserine), essential amino acid taurine and neurotransmit- ter GABA, and its analogues (20). In vitro studies in CaCo2, MDCK, and renal cells have reported taurine transporter (TauT/SLC6A6) is partially involved in the uptake of VGB 1 Institute for Drug Delivery & Biomedical Research, Bangalore, India. 2 To whom correspondence should be addressed. (e–mail: murthy@olemiss.edu) AAPS PharmSciTech (2020) 21:196 DOI: 10.1208/s12249-020-01736-7 1530-9932/20/0000-0001/0 # 2020 American Association of Pharmaceutical Scientists