Drug metabolism major pathways

Table 5-7. Experimental conditions to reduce the activity of the major drug-metabolizing enzyme pathways using the in vitro experimental systems for drug metabolism...

A new tool for computational ADME/Tox called MetaDrug includes a manually annotated Oracle database of human drug metabolism information including xenobiotic reactions, enzyme substrates, and enzyme inhibitors with kinetic data. The MetaDrug database has been used to predict some of the major metabolic pathways and identify the involvement of P450s [78]. This database has enabled the generation of over 80 key metabolic... 

The answer is b. (Hardman, pp 868 869.) Persons with low hepatic iY-acetyltransferase activity are known as slow acetylators. A major pathway of metabolism of procainamide, which is used to treat arrhythmias, is iV-acetylation. Slow acetylators receiving this drug are more susceptible than normal persons to side effects, because slow acetylators will have higher-than-normal blood levels of these drugs N-acetylprocainamide, the metabolite of procainamide, is also active. 

Drug Therapeutic category enzyme in the major pathway for metabolism of the drug Frequency of poor metabolizer genotypes, % ... 

In many other cases, hydrolysis results in drug inactivation, as with the tuberculostatic agent pyrazinamide (4.69). In humans and rats, the metabolism of this compound involves deamidation to produce pyrazinoic acid (4.70). Ring oxidation is another major pathway, leading to 5-hydroxypyrazinamide (4.71), which, in turn, is hydrolyzed to 5-hydroxypyrazinoic acid (4.72). The rates of hydrolysis were found to determine the apparent half-life of pyrazinamide [42] [43]. 

Figure 9.1. The metabolic pathways for the principal 1,4-benzodiazepines. The major pathway is shown with solid arrows and the minor pathway with broken arrows. Commercially available drugs are underlined.

When working with non-radiolabeled drugs the major challenge is to find metabolites in the biological matrices. Because the enzymes responsible for metabolism are quite well characterized metabolic changes can partially be predicted. For example hydroxylation of the parent drug is in many cases the principal metabolic pathway. From a mass spectrometric point of view it results in an increase of 16 units in the mass spectrum. In the full-scan mode an extracted ion current profile can be used to screen for potential metabolites. In a second step a product ion spectrum is recorded for structural interpretation. Ideally, one would like to obtain relative molecular mass information and the corresponding product ion spectrum in the same LC-MS run. This information can be obtained by data dependant acquisition (DDA), as illustrated in Fig. 1.39. 

Zhao, X. J. and Ishizaki, T. (1997) Metabolic interactions of selected antimalar-ial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes. Br. J. Clin. Pharmacol. 44, 505-511. 

Ann. Chem. Pharm., 63, 335 in Conti, A., and Bickel, M.H., (1977) History of drug metabolism discoveries of the major pathways in the 19th century. Drug Metabolism Reviews, 6 (1), 1-50. 

The major pathways for its metabolism include ring hydroxylation, with subsequent glucuronide conjugation and A-acetylation. Hydralazine exhibits a first-pass effect in that a large part of an orally administered dose is metabolized before the drug reaches the systemic circulation. The first-pass metabohsm occurs in the intestinal mucosa (mostly A-acetylation) and the hver. The primary excretory route is through renal elimination, and about 80% of an oral dose appears in the urine within 48 hours. About 10% is excreted unchanged in the feces. 

The drug is concentrated in estrogen target tissues, such as the ovaries, uterus, vaginal epithelium, and breasts. Hydroxylation and glucuronidation of the aromatic rings are the major pathways of metabolism excretion occurs primarily in the feces. 

The major oxidative drug-metabolizing pathway is catalyzed by cytochrome P450 enzymes (Mulder, 2006). The abbreviation CYP is typically used in this context. More than 60 CYPs have been identified. These are identified by up to four characters (letters or numbers). For example, in the term CYP2A4 4 the letters and numbers indicate the following ... 

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