Drugs, oxidative detoxification

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. 

Dmg rehabilitation programs may be either inpatient or outpatient. Inpatient, or residential, drug programs require a patient to live at the hospital or rehab facility for a period of several weeks to several months. Outpatient programs allow patients to spend part of their day at the treatment facility, and return home at night. Nitrous oxide is rapidly eliminated from the body, and abuse of NzO alone is not associated with withdrawal. This means that a lengthy detoxification period (removal of the drug from the body) is typically not required. 

While the term biotransformation generally implies inactivation and detoxification, there are exceptional cases where a metabolite is more chemically active or more toxic than the parent compound. In these situations, the processes of bioactivation and biotoxification are said to have occurred, respectively. An example of bioactivation is the formation of the commonly used drug acetaminophen from phenacetin in the liver (see Figure 3.2). The latter drug was once widely used as an analgesic agent but because of kidney toxicity has been replaced by other more potent, less toxic substitutes including, of course, acetaminophen itself. In this particular bioactivation pathway the process occurs via normal oxidative dealkylation. 

Nitric oxide formed from amyl nitrite inhibits cytochrome P450 (117) and ritonavir inhibits CYP2D6 (118), which has a major role in metamfetamine detoxification (119). This interaction could have led to fatal plasma concentrations of metamfetamine. It is therefore suggested that patients who take protease inhibitors are made aware of the potential risk of using any form of recreational drugs metabolized by CYP2D6, particularly metamfetamine. 

The enzymes are widely distributed in microorganisms, plants, and animals. " Three Mo-MPT enzymes have been found in mammals (1) xanthine dehydrogenase see Dehydrogenase) has many, varied roles in purine catabolism, drug metabolism, and oxidative stress response, (2) aldehyde oxidase is important in drug metabolism and the synthesis of retinoic acid from retinal, and (3) sulfite oxidase plays a cmcial role in the detoxification of sulfite produced in the degradation of cysteine and methionine. Genetic Mo-MPT deficiency in... 

Metabolism of the cytostatic drug cyclophosphamide (CP Fig. 1) involves hydroxylation at the C-4 position by cytochrome P450. Subsequently, a number of detoxification reactions can occur (oxidation to the keto derivative, dechloroethylation, formation of a carboxylic acid). The phosphoramide mustard resulting from spontaneous decomposition of 4-hydroxy-CP is thought to be the cytotoxic chemotherapeutic species. The chiral nature of the phosphorus atom resulted in a twofold greater therapeutic index (LDjq/EDjq) for the S-(-)-enantiomer (against the ADJ/PC6 plasma cell tumor in mice) without detectable differences in metabolism... 

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