Activation by CYPs

Ultrarapid metabolism of an active drug could mean that therapeutic levels are not reached, while poor metabolism will increase the likelihood of adverse events at normal doses because of resulting increased levels of the drug. Conversely, for prodrugs that must first be activated by CYP enzymes, ultrarapid metabolism may increase adverse effects, while poor metabolism may result in little response. 

PAHs are metabolized by a variety of xenobiotic-metabolizing enzymes (Baird et al., 2005). CYP and epoxide hydrolase eonvert the PAH into PAH-diols and these products are transformed in metabolites, potentially, carcinogenic, by the CYP aetion, forming PAH diol-epoxides or by the Aldo-keto-reductase action, generating PAH o-quinones. PAHs can be also activated by CYP and by peroxidases, forming the reactive cations radicals, which bind, covalently, to DNA. Intermediary products formed are still metabolized by enzymes of phase 11, resulting in metabolites more polars and soluble in water becoming ready to be excreted by the body (Shimada, 2006). 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

Association to allopurinol, amiodarone, fluoroquinolones, carbamazepine, pheno-barbital, rifampicin, and others Inhibition of CYP activity by the drugs... 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

The activity of CYP enzymes is also influenced by external factors such as food and other drugs taken concomitantly ... 

PAHs are known to undergo covalent binding to macromolecules. They are potent inducers of Cyt P450. [17]. They can also be activated twice by CYP to dihydrodiol peroxides. Carcinogenicity is affected by both the number of rings and the methyl substitution, so that the toxicity pattern for the series below is as shown below [18], with toxicity increasing to the right (two separate series of molecules) ... 

In addition to activations catalyzed by CYPs and FMOs, phase two conjugations, cooxidation by COX during prostaglandin biosynthesis, and metabolism by intestinal... 

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Three of the human metabolites of donepezil have not undergone extensive safety tests in animals. These comprise two O-demethylated derivatives and an N-oxidation product. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable. These findings are consistent with the results from formal pharmacokinetic studies which showed that donepezil and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin... 

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