Nursing Pharmacology Chapter 2: General Principles: Pharmacokinetics
Mixed function oxidase System (cytochrome 450 System)--Phase I Reactions
Microsomes have been used to study mixed function oxidases
Drug metabolizing enzymes are located in lipophilic, hepatic endoplasmic reticulum membranes. Smooth endoplasmic reticulum contains those enzymes responsible for drug metabolism.
One molecule oxygen is consumed per substrate molecule
One oxygen atom -- appears in the product; the other in the form of water
Following repeated administration, some drugs increase the amount of P450 enzyme usually by:
Increasing enzyme synthesis rate (induction) and/or
Decreasing enzyme degradation rate (the rate at which the enzyme is degraded to inactive forms by the cell).
Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:
Cimetidine (Tagamet) (anti-ulcer --H2 receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:
Other coadministered drugs
Mechanism of Action: competitive inhibition
Catalytic inactivation of cytochrome P450.
Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)) are metabolized by a cytochrome P450:
The antibiotic metabolites complex with cytochrome heme-iron which results in a complex that is catalytically inactive.
Chloramphenicol (Chloromycetin) is metabolized by cytochrome P450 to a reactive, alkylating metabolite that itself inactivates cytochrome P450.
Mechanism of Action: Some drugs target the heme (Iron) component and inactivate.
Ethinyl estradiol (Estinyl)
Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.
Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27
Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61