Enzyme inhibitors drug metabolism

A substrate is a substance that is acted upon and changed by an enzyme. An enzyme inducer accelerates metabolism of co-prescribed drugs which are substrates of the same enzyme, reducing their effect. An enzyme inhibitor retards metabolism of co-prescribed drugs, increasing their effects (see Chapter 7, Metabolism). Competition between drugs that are substrates for the same enzyme may retard their metabolism, increase plasma concentration and iead to enhanced therapeutic or adverse effects. 

A new tool for computational ADME/Tox called MetaDrug includes a manually annotated Oracle database of human drug metabolism information including xenobiotic reactions, enzyme substrates, and enzyme inhibitors with kinetic data. The MetaDrug database has been used to predict some of the major metabolic pathways and identify the involvement of P450s [78]. This database has enabled the generation of over 80 key metabolic... 

CYP2C19 is another example of the existence of both cross-ethnic and inter-individual variations in drug metabolism. This enzyme is involved in the metabolism of many psychotropics such as diazepam and tertiary tricyclic antidepressants, as well as one of the selective serotonin re-uptake inhibitors (SSRIs), citalopram. Using S-mephenytoin as the probe, previous studies showed that up to 20% of East Asians (Chinese, Japanese, and Koreans) are PMs, when only 3-5%... 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

Hollenberg, P.F. (2002) Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metabolism Reviews, 34 (1-2), 17-35. 

Fontana, E., Dansette, P.M. and Poli, S.M. (2005) Cytochrome P450 enzymes mechanism based inhibitors common sub-structures and reactivity. Current Drug Metabolism, 6, 413 -54. 

Enzyme inhibitors are chemicals that may serve as a natural means of controlling metabolic activity by reducing the number of enzyme molecules available for catalysis. In many cases, natural or synthetic inhibitors have allowed us to unravel the pathways and mechanisms of intermediary metabolism. Enzyme inhibitors may also be used as pesticides or drugs. Such materials are designed so that they inhibit a specific enzyme that is peculiar to an organism or a disease state. For example, a good antibiotic may inhibit a bacterial enzyme, but it should have no effect on the host person or animal. 

Many substances can affect metabolic processes by influencing the activity of enzymes. Enzyme inhibitors are particularly important here. A large proportion of medicines act as enzyme inhibitors. Enzyme-kinetic experiments are therefore an important aspect of drug development and testing procedures. Natural metabolites are also involved in regulatory processes as inhibitors (see p.ll4). 

Antimetabolites are enzyme inhibitors (see p. 96) that selectively block metabolic pathways. The majority of clinically important cytostatic drugs act on nucleotide biosynthesis. Many of these are modified nucleobases or nucleotides that competitively inhibit their target enzymes (see p. 96). Many are also incorporated into the DNA, thereby preventing replication. 

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