CYP enzyme system

Most pharmacokinetic interactions in transplantation occur due to interactions with the CYP enzyme system however, several interactions have been shown to occur via alternative mechanisms. One of the most notable is that seen between tacrolimus and some of the prokinetic agents. Cisapride and metoclopramide have been shown to increase the absorption of tacrolimus by enhancing gastric emptying.41... 

CYP3A. DP7 is now considered a lead compound for the development of novel DHPs which do not affect CYP enzyme system but still retain the activity towards ABC-efflux transporters [110, 111]. Cardiac effects of DP7 using... 

St. John s wort has been shown to have many interactions with other drugs. Although one study found that St. John s wort has no effect on the cytochrome P450 (CYP) enzyme system (62), most studies have shown it is a... 

The future of psychopharmacotherapy may include creative dietary or other pharmacological manipulations of the CYP enzyme system to achieve a positive treatment response. Recently, it was demonstrated that levels of cyclosporine (an expensive immunosuppressive agent) were dramatically increased in patients who were concomitantly administered grapefruit juice (Hollander et al. 1995). In other studies, paroxetine and fluoxetine were used to raise desipramine levels in superextensive me-tabolizers who were nonresponsive to standard doses (Kraus et al. 1996). Also, the authors used fluvoxamine to augment olanzapine and clozapine concentrations when a lack of response was obtained at standard or upper-level doses. Because per-pill costs of many of today s newer-generation psychoactive compounds often prove prohibitive, use of dietary and pharmacological CYP inhibitors could have significant pharmacoeconomic implications. 

The cytochrome P450 (CYP) enzyme system is a key player in methadone metabolism, and research is aimed at discovering which isoenzymes have the most influence. Although its metabolism is complex and research is incomplete, methadone appears to be metabolized mainly by CYP2B6 [52-54]. Testing for this isoenzyme may help identify who is at risk for slow metabolism and, therefore, toxicity from drug accumulation. 

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... 

Disulfiram inhibits CYP enzymes 1A2, 2C9, and 3A4 many benzodiazepines are metabolized via these pathways lorazepam, temazepam, and oxazepam are NOT metabolized via the CYP4S0 system and are reasonable alternatives. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

The majority of antiretroviral medications are metabolized by the cytochrome P-450 enzyme system (CYP). Therefore, it is important to review patient medication profiles for drugs that may interact with antiretroviral drugs. 

Human CYPs are multicomponent enzyme systems, requiring at a minimum the CYP enzyme component and a reductase component to be functional. The reductase requires a reduced nicotinamide cofactor, typically NADPH, and this cofactor must be regenerated to provide a steady supply of reducing equivalents for the reductase. Regeneration is accomplished with a separate substrate and enzyme. Glucose-6-phosphate and glucose-6-phosphate dehydrogenase have been widely used for this purpose. The overall complexity of the reaction mixtures and their cost have been barriers to the widespread use of recombinant human CYPs for metabolite synthesis in the past. 

The experiment was conducted in the presence of the fungus and the compound ABT at sufficiently high concentration, 5 mM, to cause the inhibition of Cyp P450 enzyme system expression by the fungus. 

The catalytic activity of CYP enzymes requires functional coupling with its redox partners, cytochrome P450 NADPH oxidoreductase (OR) and cytochrome bs. Measurable levels of these two proteins are natively expressed in most cell lines. Therefore, introduction of only the CYP cDNA is generally needed for detectable catalytic activity. However, the levels of expression of the redox partner proteins may not support maximal CYP catalytic activity, and therefore enhancement of OR levels may be desirable. This approach has been used successfully with an adenovirus expression system in LLC-PKi cells [12],... 

In general, the CYP enzymes have low substrate specificity compared to other protein systems in the human body. General rules have been described in the literature... 

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