title: The molecular mechanism of intestinal levodopa absorption and its possible implications for the treatment of Parkinson's disease.
abstract: 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. l-DOPA 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, coadministration of l-DOPA and dietary amino acids is avoided to decrease competition for transport in intestine and at the blood-brain barrier. l-DOPA is routinely coadministered 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 Madin-Darby canine kidney epithelia expression systems and ex vivo preparations from wild-type and knockout mice, we identified the neutral and dibasic amino acids exchanger (antiporter) b(0,+)AT-rBAT (SLC7A9-SLC3A1) as the luminal intestinal l-DOPA transporter. The major luminal cotransporter (symporter) B(0)AT1 (SLC6A19) was not involved in levodopa transport. L-Leucine and L-arginine competed with levodopa across the luminal enterocyte membrane as expected for b(0,+)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 l-DOPA 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 prodrug.
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.) simonemc@physiol.uzh.ch.
authors: Simone M R
authors: SM
authors: Camargo
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: Raphael N
authors: RN
authors: Vuille-dit-Bille
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: Luca
authors: L
authors: Mariotta
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: Tamara
authors: T
authors: Ramadan
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: Katja
authors: K
authors: Huggel
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: Dustin
authors: D
authors: Singer
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: Oliver
authors: O
authors: Götze
authors: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (S.M.R.C., R.N.V.-d.-B., L.M., T.R., K.H., D.S., F.V.); and Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland (O.G.).
authors: François
authors: F
authors: Verrey
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism*; D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D004285:Dogs; D006801:Humans; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D007980:Levodopa / Q000493:pharmacokinetics*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D014981:Xenopus
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; D000978:Antiparkinson Agents; D007980:Levodopa