CYP isoforms

The levels of exposure to phenobarbital in humans from therapeutic uses are comparable to serum levels that produce tumorigenic effects achieved in animals. Based on these analyses, the first key event, induction of CYP isoforms (CYP3A as well as CYP2B), occurs in humans at the levels of exposure that humans attain... 

Based on the in vitro results and the rat in vivo studies at different exposure levels, induction of CYP isoforms in human hepatocytes is considerably lower for metofluthrin than phenobarbital at identical concentrations [115, 116]. 

Extensive metabolism studies carried out mainly in rats and mice show that pyrethroids are metabolized by oxidation and ester cleavage, which are mediated by CYP isoforms and carboxylesterases, respectively. CYP isozymes and carboxylesterases responsible for the metabolism are reviewed below. 

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

Shin, J.G., Soukhova, N. and Flockhart, D.A. (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro preferential inhibition of CYP2 D6. Drug Metabolism and Disposition, 27 (9), 1078-1084. 

Scheme 11.2 Mechanism-based inhibitors on human CYP isoforms.

Figure 12.5 Three MBIs ((a) paroxetine, CYP2D6 (b) furafylline, CYP1A2 (c) erythromycin, CYP3A4) [30] and three substrates ((d) MBDB, CYP2D6 (e) dantrolene, CYP3A4 (f) adinazolam, CYP3A4) of different CYP isoforms.

The limited availability of suitable human tissue for experimental studies and the rather low CYP expression level in the human lung, compared to that found in rodents [111], have notably limited identification of the lung CYP isoforms. By means of RT-PCR, it has been possible to qualitatively demonstrate the presence of several CYP mRNAs in the human bronchial mucosa, namely CYP1A1, 2A6, 2B6, 2C, 2E1 and 3A5, whereas the expression of CYP1A2, 2D6, 3A4 and 3A7 could be detected only in some samples (Table 10.1) [109, 111, 112], Immunohistochemical analysis has shown the significant expression of CYP enzymes in different pulmonary cells including... 

Metabolism - In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome P450 (CYP) isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. 

Metabolism - Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in 2 inactive metabolites. Linezolid is not detectably metabolized by human cytochrome P-450 and it does not inhibit the activities of clinically significant human CYP isoforms. 

In this part of the chapter, QSAR models developed to predict or interpret the metabolism of the CYP enzyme will be explored. The following sections are structured according to individual CYP isoforms and the various types of descriptors and algorithms used to develop the models. 

A number of different approaches, have been designed to characterize the metabolic clearance of compounds, namely antibody inhibition, correlation analysis, chemical inhibitors and cDNA-expressed CYPs. As expected the science underlying these tools has developed over the past two decades reducing the need to use several approaches simultaneously to make unequivocal conclusions regarding the CYP isoform responsible for the metabolism of a drug of interest. For the purposes of the current chapter, only the latter two are discussed. The readers are referred to recent reviews that describe in detail the science behind antibody inhibition and correlation analysis [87-89]. 

CYP3A4 is thought to be the most predominant CYP isoform involved in human drug metabolism, both in terms of the amount of enzyme in the liver and the variety of drugs that are substrates for this enzyme isoform. 

Representative Drugs Metabolized by Each of the CYP Isoforms in Human Drug Metabolism... 

Table 4.4 lists representative inducers of each of the CYP isoforms. No inducers of CYP2D6 have been identified. 

Flavonoids, especially flavones and flavonols, also directly bind to several CYP isoforms (lAl, 1A2, IBl, 3A4) involved in xenobiotics metabolism and inhibit enzyme activity. Structure-activity relationships show rather high isoform selectivities depending on the flavonoid substitution pattern and contrasted inhibition mechanisms. For instance, inhibition by flavonoids of 7-methoxyresorufin O-demethylation in microsomes enriched in CYP lAl and 1A2 reveals that galangin (3,5,7-trihydroxyflavone) is a mixed inhibitor of CYP 1A2 (.ST = 8 nM) and a five times less potent inhibitor of CYP 1A1. By contrast, 7-hydroxy flavone is a competitive inhibitor of CYP lAl (Aii = 15 nM) and a six times less potent inhibitor of CYP 1A2. In addition, fairly selective inhibition of CYP IBl (specifically detected in cancer cells) by some flavonoids has been reported. For example, 5,7-dihydroxy-4 -methoxyflavone inhibits IBl, 1 Al, and 1A2 with IC50 values of 7, 80, and 80 nM, respectively. ... 

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