Prodrug disposition

OH Drummer, B Jarrott. Captopril disulfide conjugates may act as prodrugs Disposition of the disulfide dimer of captopril in the rat. Biochem Pharmacol 33(22) 3568-1571, 1984. 

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

Moussa, C., Houziaux, P., Danree, B. and Azerad, R. (1997) Microbial models of mammalian metabolism. Fungal metabolism of phenolic and nonphenolic p-cymene-related drugs and prodrugs. I. Metabolites of thymoxamine. Drug Metabolism and Disposition The Biological Fate of Chemicals, 25, 301-310. 

These various examples underline various aspects of the metabolism and disposition of lactones in connection with their pharmacological or toxicological activities. Other cases also exist, namely the lactone prodrugs to be presented in Chapt. 8. 

B. J. Aungst, M. J. Myers, E. Shefter, E. G. Shami, Prodrugs for Improved Oral Nalbuphine Bioavailabihty Inter-Species Differences in the Disposition of Nalbuphine and Its Acetylsalicylate and Anthranilate Esters , Int. J. Pharm. 1987, 38, 199 - 209. 

T. C. Burnette, P. de Miranda, Metabolic Disposition of the Acyclovir Prodrug Valacic-lovir in the Rat , Drug Metab. Dispos. 1994, 22, 60-64. 

Falkner FC, Twomey TM, Borgers AP, Garg D, Weidler D, Gerber N, Browder IW. Disposition of ampiroxicam, a prodrug of piroxicam, in man. Xenobiotica 1990 20(6) 645-52. 

Nakamura, M., Kawakita, Y., Yasuhara, A., et al. (2006) In vitro and in vivo evaluation of the metabolism and bioavailability of ester prodrugs of MGS0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid), a potent metabotropic glutamate receptor antagonist. Drug Metabolism and Disposition, 34, 369-374. 

Collectively, our results show that mCESl is very, simiiar to hCE-1, Therefore, mCESl is thought to be one of the critical determinants for pharmacokinetics and pharmacodynamic actions of ester prodrugs as well as ester drugs. This work provides useful information for the study of metabolism and dispositions of ester prodrugs as well as ester drugs. 

The body provides an intensely chiral environment in which the great majority of important processes exhibit stereospecificity. The disposition of xenobiotics is determined by their interaction with highly chiral endogenous molecules such as transporters and enzymes. Therefore the site-specific delivery of a drug can be achieved through the prodrug approach... 

Yoshigae, Y. Imai, T. Aso, T. Otagiri, M. Species differences in the disposition of propranolol prodrugs derived from hydrolase activity in intestinal mucosa. Life Sci. 1998, 62, 1231-1241. 

Fukuhara, A. Imai, T. Otagiri, M. Stereoselective disposition of flurbiprofen from a mutual prodrug with a histamine H2-antagonist to reduce gastrointestinal lesions in the rat. Chirality 1996, 8, 494-502. 

Hosokawa, M., Watanabe, N., Tsukada, E., Fukumoto, M., Chiba, K., Takeya, M., Imai, T., Sasaki, Y.F. Sato, T. (2001) Multiplicity of carboxylesterase isozymes in mammals and humans role in metabolic activation of prodrugs. Yakubutsu Dotai (Xenobiotic Metabolism and Disposition), 16(suppl.), 92-93. 

Lan S, Hsieh DC, Hillyer JW, Fancher RM, Rinehart KJ, Warrack BM, White RE (1998) Metabolism of a-phosphonosulfonate squalene synthase inhibitors. I. Disposition of a famesylethyl a-phosphonosulfonate and ester prodrugs in rats. Drug Metab Dispos 26 993-1000... 

Vickers, S. Duncan, C.A. Chen, I.W. Rosegay, A. Duggan, D.E. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab.Dispos., 1990, 18, 138-145 [plasma tissue mouse dog human SPE gradient liver prostate testes adrenal kidney lung, spleen forestom ... 

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