Enzyme inhibition drugs causing

Drug-drug interactions mediated by enzyme induction are less common than those mediated by enzyme inhibition. Drug-drug interactions due to enzyme induction are also less likely to cause safety issues, except toxic if a toxic metabolite is formed by metabolite activation, however, they may affect... 

Sometimes CYPs can also produce reactive metabolite species that, instead of undergoing the normal detoxification pathway, can act as irreversible CYP inhibitors, thus causing toxicity. Such reactive metabolites that cause CYP inactivation are called MBI and are described in Chapter 9. Mechanism-based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzymes before activity is restored. The consequences of MBI could be auto-inhibition of the clearance of the inactivator itself or prolonged inhibition of the clearance of other drugs that are cleared by the same isozyme. There may also be serious immunotoxicological consequences if a reactive intermediate is covalently bound to the enzyme. Therefore, screening of new compounds for MBI is now a standard practice within the pharmaceutical industry. 

The major distinguishing characteristic among the SSRIs is CYP enzyme inhibition. Fluvoxamine, fluoxetine, and paroxetine produce substantial inhibition of one or more CYP enzymes, whereas citalopram and sertraline do not (Table 7-29). In fact, fluvoxamine, fluoxetine, and paroxetine have all caused fatal drug-drug interactions via such CYP enzyme inhibition (339, 496, 497). 

Tiagabine is 90-100% bioavailable, has linear kinetics, and is highly protein-bound. The half-life is 5-8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve (see Chapter 3). Hepatic impairment causes a slight decrease in clearance (and may necessitate a lower dose), but the drug does not cause inhibition or induction of hepatic... 

Other drugs classified as plant alkaloids include etoposide, irinotecan, teniposide, and topotecan (see Table 36 1). These drugs inhibit specific enzymes known as topoisomerase enzymes, which are necessary for DNA replication.11 Inhibition of these enzymes causes a break in both strands of the DNA double helix, which leads to DNA destruction and cell death. Etoposide and teniposide inhibit the topoisomerase I form of this enzyme, and irinotecan and topotecan inhibit the topoisomerase II form of this enzyme. These drugs are therefore used to limit cell division and cancer growth in various types of neoplastic disease (see Table 36-4). 

There are only a few published reports of serious toxicities caused by drugs as a result of drug-drug interactions with phase II metabolic enzymes. This in part may reflect less attention given to these enzymes and/or lesser extents of induction and inhibition of these enzymes by drugs (chap. 4). 

Inhibition of RNA polymerase is a direct consequence of the binding of the drug to the enzyme on the one hand, enzyme inhibition only occurs, when the ansamycin is bound, and on the other hand, drug binding never seems to occur without causing inhibition. 

From a clinical point of view, adverse drug interactions (therapeutically undesirable effects) are particularly important. These interactions reduce or enhance the effects of a drug, causing emergence of toxic symptoms or pharmacological action qualitatively different from that expected. Undesirable interactions require specific control of therapy or even modification of doses, and are a result of a variety of mechanisms and the impact of the patient s individual characteristics on drug metabolism. Sometimes completely unfamiliar or unusual mechanisms underlie two types of reactions, positive or adverse. Most often, however, these reactions are nothing other than repeated, sometimes very well-known, pharmacokinetic processes (pharmacokinetic interactions), most of which are a result of inhibition or induction of metabolic enzymes. 

The diet contains an almost infinite number of foreign chemicals, and the enzymes of drug biotransformation probably evolved to cope with these chemicals. Consequently they were already available to deal with subsequently developed drugs. The activities of these enzymes can be affected by dietary constituents that may serve to increase or decrease them or cause both effects in alcohol ingestion, enzyme activities show a short-term decrease (inhibition) and then increase (induction). They can also be affected by nutritional status and reflect protein, fat, carbohydrate, mineral, and vitamin intake. 

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