Inhibition and Induction of Cytochrome P450 and the Clinical Implications

Abstract

The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an important role in the oxidative metabolism of drugs. Each CYP isoform possesses a characteristic broad spectrum of catalytic activities of substrates. Whenever 2 or more drugs are administered concurrently, the possibility of drug interactions exists. The ability of a single CYP to metabolise multiple substrates is responsible for a large number of documented drug interactions associated with CYP inhibition. In addition, drug interactions can also occur as a result of the induction of several human CYPs following long term drug treatment. The mechanisms of CYP inhibition can be divided into 3 categories: (a) reversible inhibition; (b) quasi-irreversible inhibition; and (c) irreversible inhibition. In mechanistic terms, reversible interactions arise as a result of competition at the CYP active site and probably involve only the first step of the CYP catalytic cycle. On the other hand, drugs that act during and subsequent to the oxygen transfer step are generally irreversible or quasi-irreversible inhibitors. Irreversible and quasi-irreversible inhibition require at least one cycle of the CYP catalytic process. Because human liver samples and recombinant human CYPs are now readily available, in vitro systems have been used as screening tools to predict the potential for in vivo drug interaction. Although it is easy to determine in vitro metabolic drug interactions, the proper interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles. From the viewpoint of drug therapy, to avoid potential drug-drug interactions, it is desirable to develop a new drug candidate that is not a potent CYP inhibitor or inducer and the metabolism of which is not readily inhibited by other drugs. In reality, drug interaction by mutual inhibition between drugs is almost inevitable, because CYP-mediated metabolism represents a major route of elimination of many drugs, which can compete for the same CYP enzyme. The clinical significance of a metabolic drug interaction depends on the magnitude of the change in the concentration of active species (parent drug and/or active metabolites) at the site of pharmacological action and the therapeutic index of the drug. The smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences. Thus, careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential.

Cytochrome P450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver

“…As a control, peripheral blood was collected from healthy volunteers consisting of 20 males (mean: 35.7 years old, 31-46 years old). Those were composed of 10 smokers, 1 ex-smoker and 9 non-smokers, and 11 alcohol drinkers and 9 non-drinkers according to the definitions of the M Present addresses: 8 Zoology Department, Faculty of Science, Al-Azhar University (Assiut Branch), Assiut, Egypt. 9 To whom correspondence should be addressed.…”

“…Approximately 70% of human liver CYPs is accounted for by CYP1A2, 2A6, B6, 2C, 2D6, 2E1 and 3A. 8) Here, we measured the expression levels of 19 CYP genes, i.e., CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 3A4, 3A5, 3A7, 4A11, 4B1 and CYP27, by real-time reverse-transcription (RT)-PCR. Furthermore, we compared the CYP gene expression levels in tumor and non-tumor tissues from liver cancers to assess whether carcinogenesis is associated with specific changes in CYP gene expression levels or not.…”

Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

“…Approximately 70% of human liver CYP is accounted for by CYP1A2, CYP2A6, CYP2B6, CYP2C, CYP2D6, CYP2E and CYP3A enzymes (21). CYP3A is the most abundantly expressed subfamily in the liver, comprising 25 to 40% of the total CYP.…”

Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

“…High inter-individual variations in the activity profiles of these isoforms have clinical implications such as altered pharmacokinetics leading to increased adverse drug reactions or drug-drug interactions [8]. Failure of therapy occurs for drugs requiring activation by CYP-catalyzed reactions.…”