CYP systems

Several kinetic parameters can be measured on different experimental systems to account for the interaction of a compound with CYPs. For example when studying the metabolic stability of a compound, it could be measured in a recombinant CYP system, in human liver microsomes, in hepatocytes and so on. Each system increases in biological complexity. Although in the recombinant CYP system only the cytochrome under consideration is studied, in the case of the human liver microsomes, there is a pool of enzyme present that includes several CYPs, and finally in the hepatocyte cell system, metabolizing enzymes play an important role in the metabolic compound stability. In addition, transport systems are also present that could involve recirculation or other transport phenomena. The more complex the experimental system, the more difficult it is to extract information on the protein/ligand interaction, albeit it is closer to the in vivo real situation and therefore to the mechanism that is actually working in the body. 

It is of note that Hypericum, often described as the natural Prozac, has the opposite effect of fluoxetine— and selective serotonin reuptake inhibitors (SSRIs) in general—on the CYP system. Fluoxetine inhibits several CYP isoenzymes, potentially resulting in increased blood levels of drugs metabolized through this pathway (See Chapter 22). 

Drug Protein binding Haif-iife (hours) Relations to cytochrome P450 (CYP) system other key features... 

As far as protein binding and elimination route all scaffolds seem comparable, whereas all molecules with the exception of raloxifene (1) have significant interaction with the CYP system. Finally, raloxifene (1) has a significantly higher volume of... 

Nucleoside reverse transcriptase inhibitors are not significantly metabolized by the CYP system. 

N. J. and Gourgiotis, L., Hormonal effects on drug metabolism through the CYP system perspectives on their potential significance in the era of pharmacogenomics, Curr. Drug Targets Immune Endocr. Metabol. Disord. 5, 439-448, 2005. 

The cytochrome P450 (CYP) system is the group of enzymes of most interest to psychiatrists. These enzymes show considerable genetic variation, and certain isozymes can be induced by specific substrates such as phenobarbital, ethanol, and steroids. They can also be inhibited by various medications that are potent competitive inhibitors of the enzymes (e.g., cimetidine and ketoconazole). 

Similar to the techniques used for calculation of chemical disposition parameters, in vivo biotransformation kinetic parameters of a substrate can be estimated from in vitro systems such as microsomes, freshly isolated hepatocytes, fiver slices, and isolated perfused livers (24). Intrinsic clearance or Michaelis-Menten parameters for the whole liver can also be obtained by scaling in vitro parameters based on the cytochrome P450 enzyme content (25-27). These parameters can also be estimated from in vitro data obtained from recombinant human CYP systems, and also through allometric scaling of clearance estimates from animal PBPK models. 

The microbial CYP systems were studied at the same time, with yeast CYP being reported by Lindenmeyer and Smith (1964) and bacterial CYP by Appleby (1967) The systems were viewed as models and this was true especially for a CYP from P. putida called P450c, (CYPlOl) that allowed this bacterium to grow on camphor as a carbon source ". In pioneering work from the... 

Gunsalus laboratory, the P450(, system allowed biochemical and biophysical investigation of the CYP catalytic cycle as well as of the genetics of a bacterial catabolic plasmid. This typical CYP system was found to require a ferredoxin and ferredoxin reductase for catalytic activity, unlike the model for eukaryote CYPs, CYP102A1 or P450g 3, which was discovered in the Fulco laboratory and consisted of a fusion polypeptide containing CYP and reductase domains. ... 

With a favorable side-effect profile, it appears to be well tolerated even in patients who are intolerant of other SSRis. Escitaiopram may possess safety advantages, in that it appears to have potential for fewer drug-drug interactions due to little effect on the CYP system, and is less highly protein-bound than other SSRis. 

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