Drug transporters are altered in brain, liver and kidney of rats with chronic epilepsy induced by lithium–pilocarpine

Abstract

Objective: Pharmacoresistance is a common problem hindering treatment of epilepsy. A possible cause for this resistance is the overexpression of efflux drug transporters, e.g. P-glycoprotein (P-gp), which may decrease extracellular antiepileptic drugs levels in brains of intractable epilepsy patients. Another transmembrane drug transporter is the organic anion transporting polypeptide 2 (Oatp2), which is colocalized with P-gp in many polarized tissues. However, a role for Oatp2 in the development of multidrug resistance has not been established. In the present work, we investigated the expression of drug transporters Oatp2 and P-gp in brain, liver and kidney of rats with chronic epilepsy induced by lithium–pilocarpine.Methods: Chronic epilepsy was elicited after status epilepticus (SE) induced by lithium–pilocarpine in adult Wistar rats. Following SE, expression of Oatp2 and P-gp protein was detected by immunohistochemistry and Western blot analysis and messenger RNA (mRNA) using reverse transcription polymerase chain reaction (RT-PCR). Levels of the drug transporters were compared in brain, liver and kidney of chronic epileptic and control rats.Results: Both Oatp2 and P-gp were expressed in the brain, liver and kidney but predominantly in the brain. In the brain, Oatp2 and P-gp immunopositive cells were observed in brain capillary endothelium and choroid plexus epithelium. Compared with control rats, Oatp2 protein expression in brain was significantly decreased, while P-gp was obviously increased in chronic epileptic rats. P-gp mRNA was also significantly higher in brains of chronic epileptic rats, whereas the expression of Oatp2 did not change. Organic anion transporting polypeptide 2 and P-gp did not change at the mRNA or protein level with epilepsy in the liver or kidney.Conclusions: Organic anion transporting polypeptide 2 and P-gp colocalized in tissues that are important in drug absorption, metabolism and excretion. Seizures seem to induce the cerebral changes of P-gp and Oatp2. However, the changes of expression of two transporters exhibit the opposite trend. Organic anion transporting polypeptide 2 might play a different role than P-gp in intractable epilepsy. Our data provide a basis for the assessment of the role of uptake transporters and efflux pumps in the development of intractable epilepsy.