Hydrolysis drug metabolism

Testa B (2006) Principles of drug metabolism 2 hydrolysis and conjugation reactions. In Taylor JB, Triggle DJ (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, Sect 5.06... 

Zenser, T.V., Lakshmi, V.M. and Davis, B.B. (1999) Human and Escherichia coli /3-glucuronidase hydrolysis of glucuronide conjugates of benzidine and 4-aminobiphenyl, and their hydroxy metabolites. Drug Metabolism and Disposition The Biological Fate of Chemicals, 27, 1064—1067. 

Determination in Biological Fluids and Tissues All the advances in pharmacokinetics and drug metabolism described in Sections 7 and 8 would not have been possible without the availability of the proper analytical methods. The following is a tabulation of publications in this field, most of which have already been discussed in Section 5. It should be mentioned that a few publications talk about aspirin blood levels, but really mean salicylate levels. The following tabulation covers only those papers where aspirin was differentiated from other salicylates by chromatography or other means. It seems that the "workhorse" for serum salicylate levels is still the colorimetric (ferric-nitrate) method of Brodie, Udenfriend and Coburn153 published in 1944, or modifications thereof. Simplified versions (cf. 206) may lead to erroneous results under certain conditions.207 The method is also applicable for urinary metabolites after proper hydrolysis (cf. 208). For other methods restricted to salicylic acid, see Section 5.61. 

While there are clear differences in substrate selectivity between the drug metabolizing hydrolytic enzymes, there is also significant overlap, i.e., they will often tend to metabolize the same substrates but at different rates. For example, pseudocholinesterase, hCE-1, and hCE-2 catalyze the hydrolysis of heroin and cocaine. 

Phase I metabolic reactions involve oxidation, reduction, or hydrolysis of the parent molecule, resulting in the formation of a more polar compound. Phase 1 reactions are mediated by the cytochrome P450 (GYP) family of enzymes. While metabolism used to be thought of as the body s detoxification process, phase I metabolites may be equally or even more pharmacologically active than the parent compound. Drug metabolism in general, and CYP-based mechanisms in particular, are discussed in detail in Chapter 5. 

The liver is the principal site of drug metabolism. Hepatic drug metabolism is usually classified into two distinct phases. Phase I reactions are oxidation, reduction or hydrolysis. One of the most important systems that catalyse oxidation are the haem-containing cytochrome P-450 enzymes. 

The chemical changes that occur during drug metabolism are usually caused by oxidation, reduction, hydrolysis, or conjugation of the original compound.28,52 60 Examples of each type of reaction are listed in Table 3-1. Each type of reaction and the location of the enzymes catalyzing the reaction are also discussed here. 

Warner A, Norman AB (2000) Mechanisms of cocaine hydrolysis and metabolism in vitro and in vivo a clarification. Ther Drug Monit 22(3) 266-270... 

Phase I The term applied to the first stage of drug metabolism, commonly involving either oxidation, reduction, or hydrolysis of the molecule. 

The classical model of drug metabolism by acetylation is the tuberculostatic drug isoniacide (isonicotinic acid hy-drazide). The metabolism of isoniazide has two interesting aspects Firstly, non-enzymatic hydrolysis of the acetyl metabolite releases acetylhydrazine, which in turn is toxic. This, then, is an example of detrimental drug metabolism (Figure 2.30a, b). 

The conversions of prontosil (azo reduction) and bacampi-cillin (ester hydrolysis), discussed in the introduction, are examples of other important reactions in drug metabolism. 

Hydrolysis in drug metabolism, 290 Hydromedin, 591 Hydromet, 663, 764 Hydromorphinol, xvii Hydromorphol, 665 Hydromorphone, 667 (metabolite), 665... 

As described in Chapter Ih drug metabolism is composed of two distinct pathways of biochemical processing/ Phase I and Phase II. Phase I is a chemical modification (typically oxidatioiy hydrolysis/ or reduction reactions) performed primarily by members of the CYP enzyme family (49). Phase II metabolism consists of the biotransformation... 

Drug metabolism occurs primarily in the liver and most commonly involves oxidation, reduction, hydrolysis, and conjugation reactions. Quantitatively, the most important hepatic enzymes are the cytochrome P450 enzymes that have been divided into families and subfamilies (e.g., CYP3A4) based on the similarity of their amino acid sequences. These enzymes are responsible for the metabolism of a large number of drugs. 

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