Prodrugs gastrointestinal absorption

D Fleisher, BH Stewart, GL Amidon. Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting. Methods Enzymol 112 360-381, 1985. 

MR Harnden, RL Jarret, MR Boyed, D Sulton, RA Vene Hodge. Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxymethyl) but 1-yl] guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 32 1738-1743, 1989. 

Due to the presence of a wide variety of esterases in various body tissues, it is not surprising that esters are the most common prodrugs used to improve gastrointestinal absorption. By appropriate esterification of molecules containing a carboxylic acid or hydroxyl group, it is possible to obtain derivatives with almost any desirable... 

Olmesartan medoxomil (5) is also a prodrug that is rapidly and completely bioactivated by ester hydrolysis to olmesartan (RNH-6270) during absorption from the gastrointestinal tract (Warner and Jarvis, 2002). Olmesartan is eliminated in a biphasic manner with an elimination half-life of 14 h. The absolute bioavailabihty of olmesartan is 26% and peak plasma concentration is reached in 1 -2 h. Following the rapid and complete conversion of 5 to olmesartan, there is virtually no further metabolism of olmesartan. Olmesartan is eliminated from the bile and kidneys in about a 60 40 ratio. 

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration. 

Amprenavir is rapidly absorbed from the gastrointestinal tract, and its prodrug can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7-11 hours). Amprenavir is metabolized in the liver by CYP3A4 and should be used with caution in the setting of hepatic insufficiency. 

Cefuroxime is also a second-generation cephalosporin resistant to some -lactamases. It is used in veterinary medicine in intramammary treatments. Cefuroxime axetil is also a prodrug active by the oral route. It is absorbed from the gastrointestinal tract and its absorption is enhanced if the compound is given after... 

In addition to the potential of liberating the active drug upon absorption, orally applicable prodrugs require a sufficient stability in the gastro-intestinal tract which is most importantly pH-dependant chemical stability. This can be studied with simulated gastrointestinal fluids (Balbach and Korn 2004). Also... 

Lee, V.H.L. Yamamoto, A. Buur, A. Bundgaard, H. Use of prodrugs to shift the absorption site of 5-fluorouracil from the upper to the lower region of the gastrointestinal tract of the albino rabbit. Proc. Int. Symp. Control. Rel. Bioact. Mater. 1989,16, 56-57. 

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