Enzyme Induction and Inhibition

Liver microsomal enzyme inducers that are lipid soluble at the physiologic pH can be classified into two general groups. Some, such as phenobarbital, tend to stimulate all enzymes others, such as 3-methylcholanthrene, tend to be selective. The administration of phenobarbital increases the amounts of NADPH-cytochrome C reductase and P-450, and the rate of P-450 reduction. In contrast, the administration of 3-methylcholanthrene increases the amount of P-450 but neither the activity of NADPH-cytochrome C reductase nor the rate of P-450 reduction. 

---

Some metabolites of curcumin (particularly tetrahydrocurcumin) may also participate in producing the observed effects of curcumin in different models because these metabolites display greater stabilities than the parent curcumin molecule at physiological pH. Recent data show similar modes of action of curcumin metabolites regarding antioxidant enzyme induction and inhibition of multidrug-resistant proteins. " Additional data indicate that curcumin may even act against other types of diseases such as atherosclerosis " " and Alzheimer s disease. " - " ... 

Interactions with other drugs likely to be administered concomitantly, including enzyme induction and inhibition... 

Benedetti, M.S. (2000) Enzyme induction and inhibition by new antiepileptic drugs a review of human studies. Fundamental S, Clinical Pharmacology, 14, 301-319. 

Biological factors species, strain, sex, genetic factors, disease and pathological conditions, hormonal influences, age, stress, diet, tissue and organ specificity, dose, and enzyme induction and inhibition. 

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". 

The influence of diet on drug metabolism, disposition, and toxicity consists of many constituent factors. Food additives and naturally occurring contaminants in food may influence the activities of various enzymes by induction or inhibition. However, these factors are discussed in a later section Enzyme induction and Inhibition. The factors with which this section will be concerned are the nutritional aspects of diet. 

There are many factors, both chemical and biological, which affect the disposition of xenobiotics. Chemical factors include size and structure, pKa, chirality, and lipophilicity. Biological factors include species, sex and strain, genetic factors, hormonal influences, disease and pathological conditions, age, stress, diet, dose, enzyme induction and inhibition, and tissue and organ specificity. All of these factors can affect the toxicity of a chemical by changing its disposition, especially its metabolism. 

Schellens JH, van der Wart JH, Brugman M, et al. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a cocktail study design. J Pharmacol Exp Ther 1989 249 638-645. 

Many drugs may increase or decrease the activity of various CYP isoenzymes in a phenomenon known as enzyme induction and inhibition. This is a major source of adverse drug interaction, since changes in CYP activity may affect the metabolism and clearance of various drugs. 

Enzymes of the hepatic microsomal system can be induced or inhibited. Enzyme induction and inhibition have greatest significance for drugs with low to moderate hepatic extraction fractions. 

Two typical phase I dmg interaction clinical trial designs are shown in Figure 20.4. Pharmacokinetic profiles are found within each subject for each substrate with and without concomitant exposure to the study dmg. These designs are applicable to both enzyme induction and inhibition effects (Figure 20.4, upper half). The same study schematic can be used to study the effects of inhibitors or inducers on the study dmg as a substrate for CYP450 systems (as illustrated in the lower half of Figure 20.4). 

FIGURE 5.7 Relationship between an NCE s metabolism, clearance, enzyme induction, and inhibition. 

Clinical Implications of Enzyme Induction and Inhibition Patients are often given several drugs at the same time. The possibility that one drug may accelerate or inhibit the metabolism of another drug should always be kept in mind. When this phenomenon occurs, the removal of an enzyme inducer could be hazardous. The following examples reveal the consequence of enzyme induction. 

---