Cytochrome P-450 CYP

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Rescriptor tabs mg tabs can be dispersed in greater than or equal to 3 oz of water to produce slurry) 200 mg tabs should be administered whole separate dosing from buffered DDI or antacids by 1 hour with hepatic impairment LFTs, headaches cytochrome P-450 (CYP) CYP3A inhibitor 51% excreted in urine (less than 5% unchanged) 44% in feces... 

Shin, J.G., Soukhova, N. and Flockhart, D.A. (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro preferential inhibition of CYP2 D6. Drug Metabolism and Disposition, 27 (9), 1078-1084. 

The nature of plants having secondary metabolites as defensive agents greatly increases the expectation that there will be interactions with other botanical products and drugs. If well-established traditional botanical products are used according to directions, they are likely a low risk. Risk increases when botanical products are combined with conventional drug therapies and lies in the possibility of unknown natural product-drug interactions. Other risks include product deviation due to misidentification of species, the lack of standardization, or adulteration. Most of the interactions have been reported with cytochrome P-450 (CYP) 3A4, but there are interactions with other metabolism enzymes and transport proteins. 

Compared to baseline saquinavir pharmacokinetic parameters obtained in period 1, the use of garlic reduced the mean saquinavir area under the concentration-time curve (AUC) by 51%, and the maximum (Cmax) and minimum (Cmin) saquinavir concentrations by 54% and 49%, respectively. After a 10-day washout, the AUC, Cmax, and Cmin values were within a range of 60% to 70% of baseline values. The magnitude of the decline in concentration might result in therapeutic failure and viral rebound in patients with HIV. Based on the pharmacokinetic parameters obtained in period 3, it also appears that garlic might have a prolonged, albeit lesser, effect on saquinavir exposure. The effects of combined treatment with other protease inhibitors that are also potent cytochrome P-450 (CYP) enzymes modulators need to be further evaluated. 

GRAPEFRUIT JUICE ACTION ON INTESTINAL CYTOCHROME P-450 (CYP) ENZYMES... 

Oxidation is by far the most important Phase I metabolic reaction. One of the main enzyme systems involved in the oxidation of xenobiotics appears to be the so called mixed function oxidases or monooxygenases, which are found mainly in the smooth endoplasmic reticulum of the liver but also occur, to a lesser extent, in other tissues. These enzymes tend to be nonspecific, catalysing the metabolism of a wide variety of compounds (Table 9.2). Two common mixed function oxidase systems are the cytochrome P-450 (CYP-450) and the flavin monoxygenase (FMO) systems (Appendix 12). The overall oxidations of these systems take place in a series of oxidative and reductive steps, each step being catalysed by a specific enzyme. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co-enzymes. 

The impact of plant products on the metabolism of synthetic dmgs results from the inhibition or activation of cytochrome P-450 (CYP) enzymes. Evaluation of the potential activation of CYP by administration of natural plant products or dietary supplements is important for prediction of interactions between their components and dmgs. Therefore, attention is directed to research on the impact of products available on the food market known as natural non-nutritive substances on dmg absorption. Non-nutritive dietary components are mainly secondary plant metabolites, which include, among others, phenolic compounds such as phenolic acids and flavonoids. The health effects of non-nutritive substances are not yet known. So far, there is no answer on the extent to which they are absorbed and metabolized by the body, and there is no information on the permitted daily intake for these compounds. This information is particularly important because certain non-nutritive natural substances are simultaneously considered to be anti-nutritional factors, mainly because they inhibit digestion and reduce the bioavailability of nutrients or dmgs. It is also possible that they form undesirable interactions with dmgs. The positive health effects of non-nutritive natural substances are not only attributed to their antioxidant properties. These substances are involved in various metabolic... 

Drugs that are metabolized by the cytochrome P-450 (CYP) isoenzymes CYP2D6, CYP2C9, and CYP2C19 also exhibit genetic polymorphisms. An example of CYP2D6 metabolism is debrisoquine. In about 5-10 /o of Caucasians in North America and Europe and about 1% of Asians, 4-hydroxylation of debrisoquine is reduced, and such individuals are at increased risk for toxicity (orthostatic hypotension). Beta blockers (metoprolol and timolol), antiarrhythmic drugs (encainide and flecainide), tricyclic antidepressants... 

Delavirdine. Dclavirdine (Rescriptor)" must be u.sed with at least two additional antiretroviral agents to treat HI V-I infections. The oral ab.sorption of dclavirdine is rapid, and peak plasma concentrations develop in I hour. Extensive mctaboli.sni occurs in the liver by cytochrome P-450 (CYP) isozyme 3A (CYP 3A) or pos.sibly CYP 2D6. Bioavailability is 85%. Unlike nevirapine, which is 48%. protein bound, dclavirdine is more than 98% protein bound. The half-life is 2 to II hours, and elimination is 44% in feces. 51% in urine, and lc.ss than 5% unchanged in urine. Dclavirdine induces its own mctaboli.sm." Oral dosage forms are. supplied as a 200-mg capsule and a lOO-ing tablet. 

Nisoldipine is highly metabolized, with five major metabolites identified. As with most nf the dihydrnpyridincs. the cytochrome P-450 (CYP) 3A4 iso/yme is mainly responsible for the mctabnlism of nisoldipine. The major bintran.sfor-matinn pathway appears to involve the hydnixylation of the isnbutyl ester side chain. This particular metabolite has approximately 10% of the activity of the parent aimpound. 

Potentially harmful drug interactions may not be identified during controlled clinical trials, due to the exclusion of patients taking concomitant medications, which are not allowed to be taken during a study. For example, terfenadine, a novel nonsedating antihistamine which was found to cause a serious and potentially fatal cardiac arrhythmia, torsades de pointes, when administered with keto-conazole or erythromycin, and this could not realistically have been expected to be identified in the clinical trial setting. The mechanism of this adverse drug interaction was found to be due to cumulation of unmetabolized terfenadine, due to inhibition of cytochrome P-450 (CYP) by ketoconazole or erythromycin the parent terfenadine molecule is usually cleared very rapidly when there is no concomitant CYP inhibitor. 

The biochemical basis for the trait is an almost complete absence of one form of cytochrome P-450, CYP 2D6. It seems that there are several mutations which give rise to the poor metabolizer phenotype. These... 

Figure 19.9 Metabolic possibilities for model compounds having representative functionality. Selected phase 1 reactions (1) Hydrolysis of various types of esters, in this case mediated by a carboxylesterase (2) N-dealkylation mediated by certain of the Cytochrome P-450 (CYP) enzymes (3) O-dealkylation mediated by certain of the CYPs and (4) Aromatic hydroxylation also mediated by certain of the CYPs. Depending upon the subtleties of their electronic and steric environments, the relative competitive biotransformation rates for these processes will generally be (1) (2) > (3) (4). Selected phase 2 reactions (5) Formation of a glucuronic acid conjugate (or in some cases a sulfate conjugate) and (6) N-acetylation. In terms of relative biotransformation rates in general (5) >> (6).

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