Abstract: Mediation of Highly Concentrative Uptake of Pregabalin by L-Type Amino Acid Transport in CHO and Caco-2 Cells

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J Pharmacol Exp Ther. 2005 Mar 15; [Epub ahead of print]

Su TZ, Feng MR, Weber ML.

Pfizer Global R & D.

Pregabalin (PGB) is a novel drug under development for the treatment of epilepsy, neuropathic pain, fibromyalgia and generalized anxiety disorder. In this study we investigated PGB transport in rats, mammalian cell lines and Xenopus leavis oocytes.

In contrast to gabapentin (GBP), PGB absorption in rats showed unique linear pharmacokinetics. PGB entered CHO and Caco-2 cells predominately via Na(+)-independent processes. Uptake of PGB was mutually exclusive with leucine, GBP and BCH, the substrates preferential for system L. The preloaded PGB in CHO cells was exchangeable with leucine, but at a lower exchange rate than that of leucine and GBP. Dixon plots showed competitive inhibition of leucine uptake by PGB with a Ki value very close to the Km value for PGB uptake (377 vs. 363 microM).

At an extracellular concentration of 300 microM, the intracellular PGB concentration in CHO cells reached 1.5- and 23-fold higher than that of GBP and leucine, respectively. By contrast, at clinically relevant concentrations, PGB appeared not to interact with GABA transport in GAT1, GAT2 and GAT3 cell lines, system y(+), b(0,+) , B(0,+) and B(0) transport activities in Caco-2 and NBL-1 cells, and the b(0,+)-like transport activity in rBAT cRNA-injected Xenopus leavis oocytes.

Taken together, these results suggest that L-type transport is the major transport route for PGB and GBP uptake in mammalian cells. The differential affinity of PGB and GBP at L-type system leads to more concentrative accumulation of PGB than GBP, which may facilitate PGB transmembrane absorption in vivo.

PMID: 15769862 [PubMed – as supplied by publisher]

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