Intestinal transport of levodopa : Implications for the therapy of Parkinson's disease

Abstract: Levodopa has been the basic treatment of patients with Parkinson's disease for the last 30 years. However, with time nearly all patients develop fluctuations in motor performance correlated to levodopa plasma concentrations.Animal studies have shown that levodopa is actively transported across the intestinal mucosa, possibly by special transport carriers for large neutral amino acids. Therefore, competition for intestinal absorption between levodopa and large neutral ammo acids is possible. It has also been speculated that levodopa is absorbed via the intestinal wall through paracellular means related to net water flux. The effect of these factors on levodopa absorption in humans has been examined in two pharmacokinetic studies. A recently developed jejunal perfusion technique, Loc-I-Gut, was utilised revealing a decreased absorption of levodopa in the presence of leucine, but no influence of net water flux on levodopa absorption. Consequently, it can be concluded that levodopa uses the same transport mechanism as the large neutral ammo acids, and that it is not absorbed in humans by passive diffusion. Intestinal absorption of levodopa and its distribution to the liver and brain were investigated using positron emissions tomography. The results indicate that in vivo oral drug absorption can be estimated using this technique and suggest a carrier mediated levodopa uptake in the liver and brain.Continuous duodenal levodopa infusions using a portable pump were introduced as an alternative treatment in very advanced parkinsonian patient. Due to the low solubility of levodopa in water a new formulation of levodopa/carbidopa was developed. Patients were repeatedly tested using clinical rating scales, videorecordings, and an objective optoelectronic system (MacReflex). According to the different evaluation systems patients showed improvement and decreased variance of their motor function. It was concluded that continuous duodenal infusion of levodopa is an alternative treatment strategy for patients withadvanced Parkinson's disease when conventional therapy has failed.