Cytochrome P enzymes can be inhibited or induced by drugs, Knowledge of the most important drugs metabolized by cytochrome P enzymes, The physician recognizes the drug interaction between warfarin and. The cytochrome P (P or CYP) isoenzymes are a group of In general, high-extraction drugs are less affected by these interactions than low-extraction drugs. . Inhibition is reduced enzyme activity due to direct interaction with a drug. Enzyme inhibition occurs when 2 drugs sharing affected by aging than any other metabolic.
enzymes Other medications P450 of by Cytochrome affected the inhibition
Data sheets on the Medsafe website www. Foetal levels of CYP3A4 expression, content and activity are very low, but appear to reach adult levels at around one year of age 1. Analyses have shown around two fold higher levels of CYP3A4 protein in female compared to male tissue samples 3 , 4. CYP3A4 is mainly located in the liver and small intestine and is the most abundant cytochrome in these organs 1.
However, CYP3A4 levels in the intestines are not correlated with those of the liver 3. Some medicines which are substrates of CYP3A4 have low oral but not intravenous bioavailability due to intestinal metabolism.
The bioavailability of these substrates is dramatically changed by inhibition, induction or saturation of CYP3A4 5. Some variability can be attributed to allelic variation. However, a functional effect of this variant has not been established 3. Hepatic and intestinal expression of CYP3A4 exhibits a unimodal distribution of activity suggesting that the population variability is not due to genetic polymorphism of the enzyme itself 2.
Nevertheless, there are indications of substantial heritability3. Variation in CYP3A4 among healthy individuals is most likely to be the result of differences in homeostatic regulatory mechanisms 2.
In disease states, the inherent variability of CYP3A4 mediated drug metabolism is potentially exacerbated by many factors including alterations in hepatic haemodynamics, hepatocellular function, nutrition, circulating hormones, as well as drug-drug interactions 2,3. It has also been increasingly recognised that inflammatory mediators associated with a range of disease states are capable of having profound effects on CYP3A4 gene expression 2.
Patients with inflammation, particularly elevated acute phase proteins such as C-reactive protein CRP have been noted to have reduced CYP3A4 function 2. This is clinically relevant in cancer patients because tumours can be a source of systemically circulating cytokines 3.
If a drug is extensively metabolised after oral administration by liver enzymes, rendering it inactive before it can be circulated high first-pass effect , then it may be tested for administration by other routes, such as by injection.
Frequently, drugs that seem desirable during development will be rendered toxic after a liver enzyme assay. However, sometimes bioactivation may be important for the efficacy of a drug, such as with the conversion of codeine to morphine. Drugs are tested to see whether they affect the activity of any CYP proteins. If they do, they must not be given in conjunction with drugs known to be cleared by those CYP proteins.
Detailed information exists regarding the metabolism and clearance of drugs by specific CYP proteins, which is useful for predicting potential drug interactions. Some useful websites are:. Table and data of human CYP proteins: Table of CYP protein alleles: Tables of metabolism, induction and inhibition of various drugs, CYP proteins and foods: Drug-drug interactions In addition to affecting its own rate of clearance, drugs can affect the rate of clearance of other drugs, causing drug-drug interactions.
Since the first report of a grapefruit juice-drug interaction by Bailey et al, grapefruit juice has been shown to increase the bioavailability of many other drugs metabolized by CYP3A4. The serum levels of lovastatin and lovastatin acid are signficantly increased when taken with grapefruit juice. The coadministration of itraconazole with simvastatin has been associated with rhabdomyolysis. Itraconazole has been shown to significantly increase the serum concentration of simvastatin and its active metabolite, simvastatin acid, in a double-blind, two-phase crossover study.
Two case reports of simvastatin-induced rhabdomyolysis in patients who received itraconazole also exist in the literature. In one case, a patient with normal renal function who had been stable on a simvastatin regimen for several months developed rhabdomyolysis after taking itraconazole for a fungal infection.
In another case, a renal transplant patient receiving cyclosporine and simvastatin developed myopathy and a markedly elevated CK level after starting itraconazole therapy. Cyclosporine has also been found to interact with simvastatin, most likely by competitive inhibition of CYP3A4. Plasma concentrations of simvastatin beta-hydroxy acid, the active metabolite of simvastatin, were found to be higher in heart transplant recipients receiving cyclosporine than in patients who had not had heart transplants both of which were receiving long-term simvastatin therapy.
The concomitant administration of cyclosporine with simvastatin in the heart transplant patients appeared to cause a reduced metabolic clearance of simvastatin and the buildup of the active metabolite. In a recent study in heart transplant recipients, the incidence of rhabdomyolysis was low 3. All patients in this study were receiving concomitant cyclosporine, azathioprine, and prednisone.
In another study, 5 kidney transplant recipients treated with cyclosporine, azathioprine, and prednisolone were given single 20 mg doses of simvastatin and compared with 5 patients treated with azathioprine and prednisolone without cyclosporine. In a case report, a renal transplant patient receiving cyclosporine and simvastatin developed rhabdomyolysis after taking clarithromycin for a soft-tissue infection.
The interaction of clarithromycin with cyclosporine resulted in markedly increased cyclosporine concentrations and an increased risk for myopathy due to simvastatin. In addition, clarithromycin may have also directly increased simvastatin concentrations. This case of myopathy was likely due to a drug interaction between simvastatin and diltiazem.
Myositis and rhabdomyolysis also developed in a patient who had been taking simvastatin for 19 weeks when the patient was started on nefazodone. Nefazodone, an inhibitor of CYP3A4, inhibited the metabolizm of simvastatin sufficiently to cause an increase in simvastatin plasma concentrations and rhabdomyolysis. Rhabdomyolysis has also been reported in a patient taking simvastatin concomitantly with the calcium channel antagonist mibefradil.
A total of 19 cases of simvastatin-induced rhabdomyolysis were reported to Hoffman-La Roche. Nine of these patients were also receiving concomitant cyclosporine. Seven reports to the US Food and Drug Administration FDA of simvastatin-associated muscle injury in patients taking mibefradil with simvastatin led the FDA to issue a Talk Paper warning of possible rhabdomyolysis with mibefradil and certain statins, and eventually to the withdrawal of mibefradil from the market in June Based on these reports, simvastatin should be administered with extreme caution to patients receiving CYP3A4 inhibitors.
Atorvastatin is also metabolized by CYP3A4. In a pharmacokinetic study, the concomitant administration of erythromycin with atorvastatin was found to produce a moderate increase in atorvastatin plasma concentrations.
The mean half-life of atorvastatin remained unchanged. The active metabolites of atorvastatin have a long half-life up to 57 hours , and their serum concentrations potentially could increase with multiple dosing.
However using specific bioanalytical methodology, much larger changes in the AUC and half-life of atorvastatin about threefold were observed in an interaction study with itraconazole. In a phase I study involving 8 patients, cimetidine had no clinically significant effects on the pharmacokinetics of cerivastatin.
The concomitant administration of cimetidine and cerivastatin appeared to be well tolerated, and no adverse events were observed. Although cimetidine appears not to interact with cerivastatin, cerivastatin may interact with other substrates or inhibitors of CYP3A4. Until relevant data are available, cerivastatin should be used prudently with other CYP3A4 inhibitors. These results suggest that the concomitant administration of fluvastatin with drugs that are CYP2C9 substrates such as phenytoin, oral anticoagulants, certain oral hypoglycemic agents, and certain nonsteroidal anti-inflammatory agents may lead to an increase in serum concentrations of these drugs.
The concomitant administration of fluvastatin with S-warfarin, for example, may inhibit S-warfarin metabolism and produce marked increases in prothrombin time measurements and bleeding. Currently, 6 case reports of increased prothrombin times and international normalized ratios INR resulting from the concomitant administration of warfarin and fluvastatin exist in the literature.
Although none of the patients experienced any clinically significant bleeding, all required a reduction in warfarin dosage in order to be within their therapeutic range. Since warfarin is metabolized by CYP2C9, it is likely that fluvastatin inhibited the metabolism of warfarin in all of these cases.
The simultaneous administration of fluvastatin with phenytoin may also inhibit the metabolism of phenytoin, such that the patient may experience symptoms of phenytoin toxicity. The concomitant administration of fluvastatin with certain oral hypoglycemics may result in poor diabetic control and low blood glucose concentrations.
Similarly, the coadministration of fluvastatin with certain non-steroidal anti-inflammatory agents may increase the frequency and severity of adverse drug reactions associated with this class of drugs, such as gastritis and nephrotoxicity.
Although there are no case reports in the literature to date with regard to these specific drug interactions, the pharmacist should be aware of the potential for these interactions to occur. This is especially important if a patient taking fluvastatin concomitantly with any of these drugs complains of increased frequency or severity of adverse drug reactions.
Pravastatin differs from the other statins in that it is highly specific for the liver. Pravastatin, which is hydrophylic, primarily inhibits cholesterol synthesis in liver cells, or hepatocytes. Since hydrophylic compounds are unable to penetrate cell membranes by diffusion or pores, a carrier-mediated transport mechanism has been postulated as the means by which pravastatin is taken up by hepatocytes.
There is also a carrier for the facilitated diffusion of glucose. Of these carrier-mediated transport systems, pravastatin has been shown to have a high affinity for the sodium-independent uptake system for bile acids. Hence the tissue selectivity of pravastatin is due to its high affinity for this bile acid transporter, which exits primarily in the hepatocyte membrane.
Role of cytochrome P450 in drug interactions
Drugs can increase or decrease the activity of one or more CYP enzymes, which can affect the rate of clearance of other drugs, causing drug-drug interactions. as bergamottin that can inhibit CYP3A4, an important CYP enzyme required to . The cytochrome P(CYP) enzyme family plays a dominant role in the enzymes. Inhibition based drug interactions form a major part of clinically significant drug interactions. .. Other factors affecting the expression of CYP. There is a longer list of other drugs that must be prescribed with great caution to Drug interactions with many antihypertensive agents that are metabolized by the Table 1 lists drugs that induce or inhibit cytochrome P enzymes for.