Scheme 7. Various strategies used to convert linear peptides with both a free N-terminus amino group and a C-terminus carboxyl group to cyclic peptides. Also shown is the metabolic pathway for conversion of an acyloxyalkoxy-based prodrug of DADLE (Tyr-D-Ala-Gly-Phe-D-Leu) to DADLE
mimetics may be well absorbed, depending on the degree of paracellular transport or their ability to be recognized by a transporter. It is also possible to deliver these polar drugs orally if they are converted to less polar prodrugs by modifying either the carboxy or the amino terminus.
Like the amino acids, many nutrients and essential vitamins are absorbed via transporter-mediated mechanisms. However, these transporters can be inhibited and, occasionally, it may be best not to rely on the transporter. An interesting example is the absorption of thiamine or vitamin B1 (42). Although thiamine, a quaternary ammonium compound, is actively transported from the GIT, its transport is depressed on acute alcohol ingestion (Thomson et al., 1971; Thomson and Leevy 1972; Thomson and Majumdar, 1981). Consequently, chronic alcoholics, due to this inhibition and poor diet, often demonstrate symptoms consistent with Wernicke's disease and the accompanying bilateral and ocular palsy resulting from thiamine deficiency (Baker et al., 1974). In Mediterranean populations, where garlic is frequently used in cooking, these symptoms are seen
nh2 42 thioesterase ^ phosphatase A
nh2 42 thioesterase ^ phosphatase A
less frequently. This has been traced to the presence in garlic of a lipid soluble form of thiamine, allithiamine (43), that acts as a lipid soluble, passively transported prodrug (Fujiwara, 1976). Japanese researchers extensively studied thiamine deficiency that was observed due to the extensive use of polished rice where rice hull removal eliminated a major thiamine source from the diet (Kawai et al., 1980). A number of prodrugs underwent extensive trials (43-45); Loew (1996) reported on the pharmacokinetics of benfotiamine (46). Their structures and modes of reversion are shown in Scheme 8.
It is now generally well recognized that active and/or facilitated transport plays an important role in oral absorption of many nutrients and some drugs (Yang et al, 2001; Majumdar et al., 2004; Oh et al., 1999; Tsuji and Tamai, 1999). Various transporters, including those needed for amino acids (Ganapathy et al., 1994), oligopeptides (Smith et al., 1993; Ganapathy et al., 1994), monosaccharides, inorganic phosphate, monocarboxylic acids (Enerson and Drewes, 2003), bile salts (Wilson, 1981), and nucleosides (Baldwin et al., 1999) have been identified. For a comprehensive general discussion of these transporters in drug absorption, the reader is directed to the following references (Oh et al., 1999; Tsuji and Tamai, 1999; Yang et al., 2001; Majumdar et al., 2004). If the structural elements of a drug result in its being recognized by one of the GIT transporters, then its oral availability will be better than predicted based on its physicochemical properties. Therefore, the intestinal absorption of certain drugs can be significantly enhanced by chemically converting them to a prodrug mimicking the natural substrates for the active transporter(s) (Oh et al., 1999; Tsuji and Tamai, 1999; Yang et al., 2001; Majumdar et al., 2004).
The best historical example of this concept is L-dopa (48), a prodrug of dopamine (47), a natural neurotransmitter whose CNS deficiency as has been linked to Parkinson's disease. Dopamine can be replaced by administering L-dopa, which in the CNS and peripherally is readily decarboxylated by dopa decarboxylase. L-dopa appears to be a substrate for the L-aromatic amino acid transporter (Shindo et al., 1973; Wade et al., 1973; Tsuji, 1999;) both in the intestine and at the blood-brain barrier (Shindo et al., 1971).
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