Levodopa (L-DOPA) is the naturally occurring precursor amino acid for dopamine and the main therapeutic agent for neurologic disorders due to dopamine depletion, such as Parkinson's disease. Levodopa absorption in small intestine has been suggested to be mediated by the large neutral amino acids transport machinery, but the identity of the involved transporters is unknown. Clinically, co-administration of levodopa and dietary amino acids is avoided to decrease competition for transport in intestine and at the blood brain barrier. Levodopa is routinely co-administered with levodopa metabolism inhibitors (dopa decarboxylase and cathechol-o-methyl transferase inhibitors) that share structural similarity with levodopa. In this systematic study involving Xenopus laevis oocytes and MDCK epithelia expression systems and ex vivo preparations from wild type and knockout mice, we identified the neutral and dibasic amino acids exchanger (antiporter) b0,+AT-rBAT (SLC7A9-SLC3A1) as the luminal intestinal levodopa transporter. The major luminal co-transporter (symporter) B0AT1 (SLC6A19) was not involved in levodopa transport. L-leucine and L-arginine competed with levodopa across the luminal enterocyte membrane as expected for b0,+AT-rBAT substrates whereas dopa decarboxylase and cathechol-o-methyl transferase inhibitors had no effect. The presence of amino acids in the basolateral compartment mimicking the postprandial phase increased transepithelial levodopa transport by stimulating basolateral efflux via the antiporter LAT2-4F2 (SLC7A8-SLC3A2). Additionally, the aromatic amino acid uniporter TAT1 (SLC16A10) was shown to play a major role in levodopa efflux from intestinal enterocytes. These results identify the molecular mechanisms mediating small intestinal levodopa absorption and suggest strategies for optimization of delivery and absorption of this important pro-drug.
- The American Society for Pharmacology and Experimental Therapeutics