Microsomal enzymes, drug induction

Key Words environmental regulation of xenobiotic metabolism, microsomal enzyme induction, activation of microsomal enzymes, drug-drug interactions, diet-drug interactions... 

As noted above, many of the AEDs induce hepatic microsomal enzyme systems and thus reduce the effectiveness of hormonal contraceptives. Women taking AEDs that may reduce the effectiveness of hormonal contraceptives should be encouraged to also use other forms of birth control. Due to induction or inhibition of sex hormone metabolism and changes in binding of hormones to sex hormone binding globulin, some AEDs may reduce fertility. For example, valproate has been associated with a drug-induced polycystic ovarian syndrome. Women who experience difficulties with fertility should seek the advice of health care professionals with expertise in fertility. 

III.a.3.2. Enzyme inhibition. A number of drugs have the potential to inhibit microsomal enzymes (Table 6). Inhibition of drug metabolism may therefore result in exaggerated and prolonged responses, with an increased risk of toxicity. The onset of enzyme inhibition is usually more rapid than induction, occurring as soon as sufficient concentrations of the inhibitor appear in the liver. Thus for drugs... 

Compared to the benzodiazepine sedative-hypnotics, secobarbital is more lethal in overdosage, has a higher tendency for abuse and addiction, and is more likely to cause drug interactions via induction of hepatic microsomal enzymes few advan-fages if any in safety or efficacy over benzodiazepines... 

Certain drugs induce the hepatic microsomal enzyme system i.e. enzyme induction, which decreases the effectiveness of other drugs, for example, if phenobarbital is suddenly discontinued without lowering the dosage of coumarin, severe hemorrhage can occur. 

Biochemical - somehow the drug has decreased availability. This is the effect of induction of the liver microsomal enzymes. The metabolism of... 

There are many factors in the environment, which may influence drug disposition, metabolism, and toxicity to a greater or lesser extent. However, as the influence of certain foreign compounds, both drugs and those in the environment, on microsomal enzymes has been well studied, this will constitute a separate section "Enzyme induction and Inhibition". 

Metabolism of antipsychotics is through two mechanisms conjugation with glucuronic acid and oxidation by hepatic microsomal enzymes. Both mechanisms of metabolism and subsequent inactivation take place in the liver. Some degree of enzyme induction may occur because of prolonged use of antipsychotics, which may be responsible for increasing the rate of metabolism of these drugs. 

In the early 1960s, during investigations on the N-demethylation of aminoazo dyes, it was observed that pretreatment of mammals with the substrate or, more remarkably, with other xenobiotics, caused an increase in the ability of the animal to metabolize these dyes. It was subsequently shown that this effect was due to an increase in the microsomal enzymes involved. A symposium in 1965 and a landmark review by Conney in 1967 established the importance of induction in xenobiotic interactions. Since then, it has become clear that this phenomenon is widespread and nonspecific. Several hundred compounds of diverse chemical structure have been shown to induce monooxygenases and other enzymes. These compounds include drugs, insecticides, polycyclic hydrocarbons, and many others the only obvious common denominator... 

Enzyme induction Barbiturates induce P-450 microsomal enzymes in the liver (see p. 14). Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on P-450 metabolism to reduce their concentration. 

Several reference compounds have been explored in the OECD endocrine disrupters programme, phenobarital and propylthiouracil being the most frequently studied (O Connor et al. 2002, Mellert et al. 2003, Cooke et al. 2004, Cho et al. 2003). The interpretation of positive findings in the rat concerning inhibition of thyroid function (which has been frequently found) presents considerable difficulty and there are many cases where such findings in rats have been shown to be of no relevance for the human (Akhtar et al. 1996, Waritz et al. 1996, Capen 1998, Poirier et al. 1999). Many drugs that act on thyroid function in rats share a mechanism of action based the induction of microsomal enzymes, which in turn may enhance the biliary excretion of thyroid hormones (Vansell and Klaassen 2001). 

THEOPHYLLINE ANTI EPILEPTICS -BARBITURATES, CARBAMAZEPINE, PHENYTOIN 1 theophylline levels. Possibly 1 carbamazepine and phenytoin levels Due to induction of microsomal enzyme activity. Theophylline 1 absorption of phenytoin May need to T dose of theophylline by 25%. Monitor for inadequate therapeutic response to carbamazepine and phenytoin. Measure levels of these drugs... 

Particularly likely to occur when a tricyclic drug, a phenothiazine, and a antiparkinsonian drug are prescribed concurrently Tricyclic drugs can interfere with the metabolism of oral anticoagulants Convulsive threshold lowered Hepatic microsomal enzyme induction Hypertension should be controlled with diuretics, p-blockers, or vasodilators before treatment of depression... 

Microsomal enzyme induction may shorten the half-life of rifampin and decrease drug concentrations of concurrently administered... 

Cigarette smoke contains minute amounts of polycyclic aromatic hydrocarbons, such as benzol nr pyrene. which are potent inducers of microsomal cytochrome P-4S0 enzymes. This induction increases the oxidation of some drugs in nnokets. For example, theophylline is metabolized more rapidly in smokers than in nonsmokers. This difference is reflected in the marked difference in the plasma half-life of theophylline between smokers (r /2 4.1 hours) and non-smokers u A 7.2 hours). Other drugs, such as phenacetin. pentazocine. and propoxyphene, also reportedly undergo more rapid metabolism in smokers than in nonsmokers. " ... 

Chlorpromazine is strongly bound to protein, crosses blood-brain barrier, and concentrates in the brain against plasma gradient. More than 90% of the drug in plasma is bound to proteins, is metabolized in the liver, and is excreted in both urine and feces. There is some evidence that chlorpromazine can cause hepatic microsomal enzyme induction, which indicates that it may accelerate its own metabolism. 

As the induction of hepatic microsomal oxidative activity by a lipid-soluble drug (e.g. phenobarbitone) or xenobiotic could decrease the duration of action of therapeutic agents that are mainly eliminated by microsomal oxidation, the effect of induction would be considered a form of biochemical antagonism. Drug-induced inhibition of microsomal oxidative activity, without adjustment of dosage of a concomitantly administered therapeutic agent that undergoes extensive hepatic metabolism, could lead to toxicity. Cimetidine, ketoconazole and chloramphenicol inhibit hepatic microsomal enzyme activity. 

Drug interactions of barbiturates are pronounced because of the induction of hepatic microsomal enzymes caused by barbiturates. 

Drug interactions secondary to microsomal, enzyme induction are frequent. 

Microsomal enzyme induction leads to an increase in the activity of enzymes present, most commonly through increases in the mass quantity of the oxidizing enzymes. The many isoenzymes of cytochrome P450 are affected variably by different enzyme-inducing drugs. For example, phenobar-bital and theophylline and polycycUc hydrocarbons induce enzyme activity differently. Two classical and clmicaUy relevant enzyme inducers can be contrasted. 

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