[26] Alteration of drug metabolism by the use of prodrugs

Nelson, Sidney D.

doi:10.1016/s0076-6879(85)12028-8

Cited by 2 publications

(1 citation statement)

References 20 publications

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“…Alternatively, a biologically inactive compound can also undergo enzymatic conversion to metabolites that are pharmacologically active. Prodrugs are compounds that fall in this category [17][18][19][20][21].…”

Section: Bioactivation To Pharmacologically Active Metabolitesmentioning

confidence: 99%

Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

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Metabolism reactions generally result in detoxification of xenobiotics and are accompanied by the formation of chemically stable metabolites, which are devoid of pharmacological or toxicological activities. However, in some cases, these reactions can convert drugs to products that are either chemically reactive or pharmacologically active, a process that is commonly referred to as metabolic activation or bioactivation . Most, if not all, functionalization and conjugation reactions can result in bioactivation. Even though all enzymes have the propensity to catalyze the metabolic activation of compounds, cytochrome P450 (P450) enzymes, which generally dominate metabolism, play a major role in the metabolic activation of drugs. The primary objective of this chapter is to provide an overview of bioactivation by P450 to pharmacologically active and chemically reactive metabolites. The common reactions that result in bioactivation of xenobiotics and consequences of bioactivation have been discussed here.

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Section: Bioactivation To Pharmacologically Active Metabolitesmentioning

confidence: 99%

Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

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Quantitative Structure−Metabolism Relationships: Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

Buchwald

Bodor

1999

J. Med. Chem.

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An attempt to quantitatively describe human blood in vitro hydrolysis data for more than 80 compounds belonging to seven different noncongener series of ester-containing drugs is presented. A parameter not yet explored in pharmaceutical studies, the inaccessible solid angle Omega(h), calculated around different atoms was used as a measure of steric hindrance, and the steric hindrance around the carbonyl sp(2) oxygen (Omega(h)(O=)) proved the most relevant parameter. The obtained final equation, log t(1/2) = -3.805 + 0.172Omega(h)(O=) - 10.146q(C=) + 0.112QLogP, also includes the AM1-calculated charge on the carbonyl carbon (q(C=)) and a calculated log octanol-water partition coefficient (QLogP) as parameters and accounts for 80% of the variability in the log half-lives of 67 compounds. A number of structures are still mispredicted, but the equation agrees very well with a recently proposed mechanism for hydrolysis by carboxylesterases. The model, with a predictive power tested here on three unrelated structures, should be useful in estimating approximate rates of hydrolysis for prodrug or soft drug candidates ahead of their synthesis.

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[26] Alteration of drug metabolism by the use of prodrugs

Cited by 2 publications

References 20 publications

Bioactivation I: Bioactivation by Cytochrome P450s

Bioactivation I: Bioactivation by Cytochrome P450s

Quantitative Structure−Metabolism Relationships: Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongener Carboxylic Esters

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