Drug cytochrome P450 family

Oral availability is a complex parameter that involves several chemical and physiological processes such as solubility, chemical stability, permeability and first-pass metabolism, to mention a few. All of these subprocesses depend on two different types of factor (i) interaction of the drug compound with certain macromolecules, such as the metabolism mediated by the cytochromes P450 family and (ii) interaction of the drug molecule with a certain chemical or biological environment, that will determine the solubility or the passive permeability. 

Drug Interactions. No modern discussion of the history of antidepressants would be complete without mention of the debate regarding potential drug interactions. As discussed more fully in Chapter 2, medications may interact in several ways, and their interactions may be helpful or harmful. The antidepressant debate has focused on the way these drugs influence the liver s ability to metabolize and thus deactivate other drugs. In particular, it is the impact of antidepressants on the liver s cytochrome P450 family of enzymes that has been so extensively discussed. 

It is self-evident that biotransformation will be reduced in patients with liver or kidney disease, in the elderly and also in neonates. In addition, pharmacogenetic differences play a considerable role in the way an individual patient metabolizes a drug. Such differences often result from polymorphisms in the cytochrome P450 family of microsomal enzymes. 

Methylphenidate is an inhibitor of drug metabolizing enzymes of the cytochrome P450 family and several interactions with drugs like some antiepileptics, antidepressants and oral anticoagulants, have been described. 

Since benzodiazepines are metabolized by the cytochrome P450 family of isozymes,1 potential inhibitors of these may produce significant increases in blood concentrations of benzodiazepines. An example of this inhibition is the drug midazolam, administered as a presurgical anesthetic. Lam et al.11 reported a mean increase in the area under the curve of midazolam by ketoconazole (772%) and nefazodone (444%) in a group of 40 healthy human subjects administered 200 mg ketoconazole per day and 400 mg nefazodone per day. The authors concluded that caution should be exercised when use of midazolam is warranted with potent CYP3A4 inhibitors.11... 

The cytochrome P450 family of enzymes is a large and diverse family of monooxygenases whose function is to oxidize organic substrates. They perform roles in the metabolism of endogenous signaling enzymes, xenobiotics, and drugs [116]. 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

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