Uptake of Prodrugs by Rat Intestinal Mucosal Cells: Mechanism and Pharmaceutical Implications

Alkaline Phosphatase: A Reliable Endogenous Partner for Drug Delivery and Diagnostics

“…Already in the 1960s drug delivery experts started to utilize ALP in order to overcome delivery problems. By the design of phosphate ester prodrugs, the poor aqueous solubility of various drugs such as estramustine [1] and prednisolone [2] could be addressed. When given orally these prodrugs rapidly dissolve in gastrointestinal (GI) fluids, yet being efficiently absorbed from the intestinal mucosa.…”

Gordon L. Amidon: Very Sustained Drug Absorption

“…Specifically, the idea involved mucosal cell brush border activation (metabolism) of amino acid prodrugs of otherwise water‐insoluble drugs by membrane‐bound aminopeptidases. The concept was to make a nonpolar drug more polar (soluble) with a nontoxic natural amino acid progroup and have the prodrug activation step occur immediately adjacent to the nonpolar membrane at the aqueous fluid interface . The absorption rate would be high, with little opportunity for precipitation as the nonpolar drug was released next to the lipophilic membrane.…”

“…The concept was to make a nonpolar drug more polar (soluble) with a nontoxic natural amino acid progroup and have the prodrug activation step occur immediately adjacent to the nonpolar membrane at the aqueous fluid interface. 104,135,136 The absorption rate would be high, with little opportunity for precipitation as the nonpolar drug was released next to the lipophilic membrane. Further, the solution concentration (driving force) would be high, given the polarity and water solubility of the prodrug and thus the dissolution and concentration of the prodrug would be expected to be high in the intestinal lumen.…”

“…By the late 1970s, Gordon was motivated to look at oral absorption much more mechanistically and turned his career interest in the direction of mechanistic mass transport analysis . This became a common theme for much of his later research work . Through the 1980s, he studied nutrient digestion and absorption, particularly for amino acids and peptides .…”

Drug Transport and Targeting

“…Traditionally, the chemical modification of a drug aims at the enhancement of solubility and permeability. For water-insoluble hydrophobic drugs, amino acid derivatives have been synthesized to increase solubility, and targeted to be converted back to the parent drugs by intestinal brush border membrane enzymes (Amidon et al, 1985;Stewart et al, 1986). For hydrophilic drugs, a common prodrug approach is to use simple esters of a polar parent drug to increase the hydrophobicity of the drug.…”