Page - (000230) - in Biomedical Chemistry: Current Trends and Developments

Phe into cells (Kanai, 1998) but can also carry amino acid-derived drugs such as levodopa, gabapentin, melphalan and baclofen (Cornford, 1992; Kageyama, 2000; Wang & Welty, 1996). Furthermore, LAT1 has been demonstrated to be able to transport amino acid prodrugs, where the amino acids have been conjugated with drug molecules which are not LAT1 substrates as such (Killian, 2007; Walker, 1994). Recently, Gynther and co-workers described a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific transporter by conjugating a model compound to L-Tyr (2) or L-Lys (3) with the hydrophilic drug ketoprofen, which is not a substrate for LAT1. The mechanism and kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. These results showed that a prodrug approach can achieve uptake of drugs via LAT1 into the brain intracellular fluid. The distribution of the prodrug in the brain parenchyma and the site of parent drug release in the brain were also shown with in vivo and in vitro studies (Gynther, 2008; 2010). Peptide transporters appear to be attractive targets in prodrug design for their high capacity, broad substrate specificity, strong expression in the intestinal epithelium and low occurrence of functional polymorphisms. Conjugating a specific amino acid with a drug can make it a substrate for PepT1 to enhance the absorption of the parent drug. Two excellent examples of marketed prodrugs that exploit carrier-mediated transport are valacyclovir (Valtrex; GlaxoSmithKline) and valganciclovir (Valcyte; Roche) (Cao, 2012). They are L-Val esters (i.e. valine as the promoiety) of acyclovir and ganciclovir, which both have limited and variable oral bioavailability owing to their high polarity. These amino acid prodrugs increased the intestinal permeation of their parent drugs by 3−10-fold, and their membrane transport was mediated predominantly through the di- and tripeptide transporter (hPepT1) expressed in intestinal epithelial cells (Han, 1998; Sugawara, 2000).