Prodrug absorption

Carrier-mediated prodrug absorption has especially focused upon the use of PepTl, and a variety of strategies using stabilized dipeptides and amino acid-based prodrugs with affinity to hPepTl appear promising. In retrospect, it has been shown that the commercially available prodrugs valaciclovir and valganciclovir are both absorbed via hPepTl, which provides evidence for the value of the carrier-mediated concept. 

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

Several types of chemical derivatives have been studied for designing oral prodrugs. The purpose of the next section is to examine various approaches for obtaining oral prodrug forms which improve the absorption and bioavailability of the parent compound. 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

AJ Repta. Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption. Pharm Res 6(6) 501-505, 1989. 

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. 

M Asgharnejad. Investigation into intestinal transport and absorption of an amino acid, amino acid analougue and its peptideomimetic prodrug. PhD dissertation, Chapter IV. pp 109-127, The University of Michigan, 1992. 

DI Friedman, GL Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats Enalapril and fosinopril. Pharm Res 6(12) 1043-1047, 1989. 

SC Chang, DS Chien, H Bundgaard, VHL Lee. (1988). Relative effectiveness of prodrug and viscous solution approaches in maximizing the ratio of ocular to systemic absorption of topically applied timolol. Exp Eye Res 46 59-69. 

VHL Lee, S Li, MF Saettone, P Chetoni, H Bundgaard. (1991). Systemic and ocular absorption of timolol prodrugs from erodible inserts. Proc Int Symp Controlled Release Bioact Mater 18 291-292. 

H Sasaki, H Bundgaard, VHL Lee. (1989). Design of prodrugs to selectively reduce systemic timolol absorption on the basis of the differential lipophilic characteristics of the cornea and the conjunctiva. Invest Ophthalmol Vis Sci 30(Suppl) 25. 

Naesens, L., Clercq, E. de, Van den Mooter, G., Kinget, R., Augustijns, P., Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption an in vitro study, Pharm. Res. 1999, 16, 1035-1040. 

Heylen, P., van den Mooter, G., Kinget, R., Drug absorption studies of prodrugs esters using the Caco-2 model evaluation of ester hydrolysis and transepithelial transport, Int. J. Pharm. 1998, 166, 45-53. 

The transporter-mediated uptake of drugs into epithelial cells is emerging as a new trend in biopharmaceutics [6]. Utilization of the intestinal epithelial transporters to facilitate the absorption of drugs or prodrugs appears to be an attractive delivery approach. The purpose of this chapter is to describe the pharmaceutical and medicinal relevances of intestinal transporters. This will provide new knowledge for strategies to enhance intestinal absorption of drugs. 

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