Резюме
Дорошенко О.В. Статини та лікарські взаємодії.
У статті розглядаються сучасні дані щодо системи цитохрому Р-450, її ролі у організмі та особливостях лікарської взаємодії при призначенні з іншими лікарськими засобами. Обговорюються особливості фармакокінетики та лікарські взаємодії окремих представників класу статинів.
Ключові слова: статини, лікарські взаємодії, цитохром Р-450.

Резюме
Дорошенко О.В. Статины и лекарственные взаимодействия.
В статье рассматриваются современные данные о системе цитохрома Р450, ее роли в организме и особенностях лекарственного взаимодействия при назначении с другими лекарственными средствами. Обсуждаются особенности фармакокинетики и лекарственные взаимодействия отдельных представителей класса статинов.
Ключевые слова: статины, лекарственные взаимодействия, цитохром Р450.

Summary
Doroshenko O.V. Statins and drug interactions.
This article represents modern data on cytochrome P-450 and its role in the body and features of drug interactions in the appointment of a various drugs. The pharmacokinetics and drug interactions of some different representatives of statin class is adduced.
Key words: statins, drug interactions, cytochrome P-450.

Рецензент: д.медн., проф. Л.М. Іванова

УДК 616-085.27

Харківська медична академія післядипломної освіти

Харьковская медицинская академия последипломного образования

Kharkov medical academy of Postgraduate Education

dorosenkoo@i.ua

Statins are prescribed to millions of patients worldwide for the treatment of dyslipidemia and prevention of cardio - vascular diseases. Statins reduce the risk of cardiovascular disease and mortality in patients at risk or existing coronary heart disease (CHD) [20, 26]. They are effective drugs and are well tolerated. In general, adverse effects associated with statin's therapy often are temporary and relatively mild [15, 26].

Often the reason of  discontinuation of statin therapy becomes fear of side effects. Meta- analysis of the largest studies of statins, including more than 30 thousand cases of surveillance average of more than 4 years, clearly showed that the overall rate of side effects of statins is about 1-3 %, which is comparable with placebo. Rhabdomyolysis on statin's therapy in the history of their use worldwide has led to no more than 100 fatalities, that is 0,15 cases per 1 million prescriptions [ 56].

Often statins are prescribed with other drugs, especially in older people receiving several drugs. Whereas hepatic metabolism of drugs is a problem drug interaction [50]. Thus drug interaction is an important factor in determining the safety profile of statins. Statins have pharmacological differences that affect their safety and potential drug interactions. The article aims to raise awareness of individual differences in the class of statins to help clinicians in selecting appropriate statin for long-term treatment.

Statins are reversible inhibitors of microsomal enzyme reductase inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), a key enzyme of cholesterol synthesis cascade, converts HMG-CoA to mevalonate in the liver [24]. All statins affect the liver: the liver is the target organ for statins because hepatocytes  are the main place of cholesterol biosynthesis, lipoprotein production and catabolism of low density lipoproteins [24, 29, 41].

During post-marketing studies of statins, elevations in hepatic transaminases were observed up to 1 % of patients [16, 26]. This increase depended on the dose and was comparable among different statins, although not significantly increased compared with placebo [16]. Most changes in the liver occur for the first 3 months of therapy and require monitoring.

Duration of statin's therapy before the onset of myopathy varies from a few weeks to more than 2 years [ 47]. Myopathy associated with statin represents a broad spectrum of disorders from mild muscle aches to severe  and restriction of movement with a significant elevation of creatine kinase [19 ]. Symptoms progress to rhabdomyolysis as long as the patient receiving the drug. Rhabdomyolysis is a syndrome that manifested by severe muscle injury and lysis, causing widespread release of myoglobin with dark brown urine. The report from the FDA showed that fatal rhabdomyolysis had been reported with a frequency of 1 death per 1 million prescriptions [ 45].

A number of studies reported the relationship of the incidence of side effects and dose of statins. Thus, according to a meta- analysis (50 studies, 5924 patients) of safety of different doses of atorvastatin (10, 20, 40 and 80 mg / day.) it is the relationship between the frequency of liver adverse events and the dose : the frequency of transaminase rise was - appropriately - 0 1% , 0% , 0.2 %, 0.5 % ( placebo - 0.2 %) [48]. However, in the  multicenter randomized trial the Treating to New Targets (TNT) shows that the side effects ( the rise of liver enzymes ) in patients receiving doses of atorvastatin 80 mg / day and 10 mg / day did not differ [43 ].

Statins often cause myopathy when taking high doses and/or in combination with fibrates, niacin and inhibitors of cytochrome P450 [25,43], in statin monotherapy myopathy incidence of less than 1 %, with their combination of niacin - 2%, with fibrates - 5 % [17]. In the case of co-administration of statins, particularly lovastatin and simvastatin with cyclosporine and other inhibitors of cytochrome P450 myopathy developed with greater frequency [17]. The risk of myopathy is increased in elderly patients and patients with hepatic impairment, renal failure, hypothyroidism, and severe infections [40 ].

Lipophilic statins such as lovastatin and simvastatin, easier to get into skeletal muscle and accumulate in them and therefore potentially more dangerous[17].

Probability and severity of myopathy increases when combined statin therapy and physical activity [12, 28]. It is assumed that 25% of patients that receive statins with high physical activity have muscle weakness, muscle pain and cramps [12].

According to one hypothesis, myopathy is a heterogeneous condition that can occur as the result of a combination of factors: the direct effects of drug, drug interactions, resulting in the enhanced effect of statins, often due to inhibition of cytochrome P450 3A4 (CYP3A4); genetic (it is believed that there is a genetic predisposition to the development of myopathy [14, 42]), metabolic and immunological characteristics of the patient [18, 49].

It is important to understand the role of drug interactions, which can be  divided into pharmacodynamic and pharmacokinetic interactions [54]. Pharmacodynamic interactions may be additive, and antagonistic. Pharmacokinetic interactions include: absorption, distribution, metabolism and excretion of drugs. Pharmacokinetic interactions can occur at any of these stages, but the system of cytochrome P-450 involved in most of the serious and fatal pharmacokinetic interactions. Drug interactions of statins increases when one drug alters the pharmacokinetics or pharmacodynamics of a drug [54]. Statins are highly selective inhibitors of  HMG -CoA reductase and do not have significant affinity for other receptor or enzyme systems. Thus on the pharmacodynamic level  statins are not prone to drug interactions. However, drug interactions can alter the pharmacokinetics of statins, ie the processes of absorption, distribution, metabolism and excretion [ 53].

The term "cytochrome  P450"  means a group of enzymes that contain heme, which function in the  complex with the  reductase, localized in the membranes of smooth EPR mainly cells of the liver and gastrointestinal tract. In addition, this system is widely represented in the kidneys, lungs, central nervous system [2, 10]. The term "cytochrome P450" comes from the maximum of  the absorption of the restored complex of cytochrome P-450 with CO at 450 nm.

Many medicinal compounds are substrate for cytochrome P-450, which is important for understanding the mechanism of drug interactions [Table 1]. Therapeutic agents can enhance or inhibit the metabolism of other medicinal compounds, as well as compete for metabolism of substrates corresponding isoforms.

Table 1. Inhibitors and inducers of cytochrome P450 [4]

All statins except pravastatin undergo metabolism by the cytochrome P-450, which is the main catalyst for the oxidation of drugs. Different statins interact with various enzymes that can alter or disrupt their elimination [3, 5, 8].

In humans, there are several dozen isoforms of cytochrome P-450. The fact that CYP3A4 and CYP3A5  responsible for the metabolic conversion of a large number of medicinal compounds ( about 56 ), and is the most representative form in human liver (30 to 60% of total P-450 in human liver ), do  CYP3A4 the most important in the therapy isoforms [54 ]. Thus,  CYP3A4 isoenzyme  is responsible for the metabolism of lovastatin, simvastatin, atorvastatin, CYP2C9 isoenzyme  is responsible for the metabolism of fluvastatin, rosuvastatin. Plasma concentrations of statins and risk of toxicity, particularly myopathy significantly increased on concomitant use of strong inhibitors of CYP3A4 ( itraconazole, erythromycin ) [5]. Itraconazole may increase the effect of simvastatin and its active metabolite in 10 times. Weak or moderate inhibitors of CYP3A4 ( verapamil, diltiazem ) may be used with caution with not large doses of CYP3A4-dependent statins [8]. Tiyenopirydyn, including clopidogrel is metabolized by CYP3A4 and may interact with statins [31]. Statins increase the concentration of warfarin and digoxin, which requires clinical monitoring. Cyclosporine inhibits CYP3A4 and other transport systems of the liver and may increase concentration of statin in plasma and the risk of myopathy [ 35]. Fluvastatin is metabolized by CYP2C9 and its exposure is increased twice on the background of inhibitors of CYP2C9 [ 3, 35].

Other isoforms that are actively involved in the metabolism of medicinal compounds are CYP2D6 ( metabolized beta blockers, tricyclic antidepressants and many other drugs ), CYP2C9 ( substrates which are S- warfarin,  ibuprofen, oral antidiabetic drugs ), CYP2C19 (substrate diazepam, tricyclic antidepressants such as amitriptyline, imipramine, anti-ulcer drug omeprazole and lansoprazole ), CYP2E1 ( typical substrate which is paracetamol and inhaled anesthetic halothane, organic solvents such as ethanol, acetone, acetonitrile, nitrosamines ), CYP1A2 ( metabolizes theophylline, clozapine, tacrine ). The situation is complicated by the very large number of isoforms of cytochrome  and the fact that most drugs metabolised by multiple pathways involving several isoforms [54 ].

There is evidence of increased prothrombin time and bleeding risk in patients receiving anticoagulants of indirect action during treatment with lovastatin and fluvastatin. In these cases, using lower doses of anticoagulants, more frequent monitoring of indicators of blood coagulation. Statins do not change the pharmacokinetics of drugs such as β - blockers, diuretics, cardiac glycosides, nonsteroidal anti-inflammatory drugs. Statins are recommended to temporarily stop in any patient with acute infections, major surgery, trauma, severe metabolic disorders.  Withdrawal  is not occur after  discontinuation the statins [53].

Concomitant use of verapamil, erythromycin and statins their concentration in the blood increased approximately 3-fold [22], whereas atorvastatin in combination with antifungal drug itraconazole increased the level of concentration in the blood, and the half-life of statins more than 2-fold [23]. Also the interaction with digoxin, which is an inhibitor of P-glycoprotein protein concentration of statins increased.

Some pharmacological agents that are used in cardiology practice,  increase the activity of cytochrome P450, resulting in lower concentrations of statins in the blood. This effect, in particular, have barbiturates, dexamethasone, omeprazole, rifampin, trohlitazol, carbamazepine, cyclophosphamide, therefore, to increase the concentration and receive lipid-lowering effect of statins is necessary to increase the dose.

The interaction of statins and warfarin results to increased blood levels of both drugs, international normalized ratio also increases, requiring more frequent controls. It is possible to combinate  statins and fibrates ( hemfybrozyl ). But the risk of side effects, such as myopathy and rhabdomyolysis is significantly increased. Unlike hemfybrozyl, fenofibrate is not metabolized by cytochrome P450, so it can be used  with statins in patients with coronary artery disease and severe hypertriglyceridemia [13 ].

Lovastatin.  It is an inactive lactone and hydrolyzed in the liver under carboxyesterase to active  β hydroxyacid form inhibits HMG CoA - reductase. β - hydroxyacid metabolite of lovastatin is metabolized to inactive metabolites by CYP3A4 [7].

Concomitant use of lovastatin with inhibitors of CYP3A4 and glycoprotein-P is very dangerous and resulting in higher concentrations and is associated with high risk of rhabdomyolysis. Itraconazole, which is an inhibitor CYP3A4 and glycoprotein-P increases the maximum concentration of β- hydroxyacid metabolite of lovastatin of 10-20 fold [32].

Simvastatin. It is also an inactive lactone. In the liver, it is converted to an active β - hydroxyacid form by hydrolysis under carboxyesterase, followed by metabolism CYP3A4 partially CYP2B6 and CYP2C9 to  inactive metabolites which are excreted in the bile [52 ].

Concomitant use of simvastatin with inhibitors of CYP3A4 can increases concentrations of simvastatin and its β-hydroxyacid metabolite. Thus, cyclosporine, erythromycin, clarithromycin increase the maximum concentration of simvastatin and its β - hydroxyacid metabolite [27, 38]. Itraconazole  increases the concentration of β - hydroxyacid metabolite of simvastatin of 17-fold [33 ].

HIV protease inhibitors - saquinavir and ritonavir are inhibitors of  CYP3A4, and increase the maximum concentration of β - hydroxyacid metabolite of simvastatin [38]. Gemfibrozil also  increases the concentration of β - hydroxyacid metabolite of simvastatin. Regular use of grapefruit  juice more than 1 liter per day increases the concentration of simvastatin in plasma. This can lead to unwanted medical reactions up to rhabdomyolysis [21].

However, the use of simvastatin with inductors CYP3A4 can lead to a decrease in its concentration and efficiency [11].

There is evidence that treatment with simvastatin reduced activity of tissue factor concentration and amount of thrombin fragments. Statins inhibit ADP-dependent platelet aggregation, inhibit the production of thromboxane, reduce the concentration of tissue plasminogen activator 1 - type.

Atorvastatin. Atorvastatin is the active drug. Mainly metabolized by CYP3A4. Concomitant administration of atorvastatin with  inhibitors CYP3A4 - itraconazole, ritonavir, erythromycin and clarithromycin, cyclosporine, hembibrozil can lead to  increases concentration of atorvastatin and  risk of adverse effects [ 24].

Recently, it is discussed the possible interaction of clopidogrel and atorvastatin. Clopidogrel  metabolized by CYP3A4 to an active 2 - oksaclopidogrel that blocks ADP - platelet receptors. Atorvastatin is also metabolized by CYP3A4, but not to the active metabolites. In a study [6 ], performed in vitro in liver microsomes have shown that atorvastatin is  inhibited 90% of biotransformation of clopidogrel to an active 2 - oksaclopidogrel. The authors said about " metabolic " competition between clopidogrel and β - hydroxyacid metabolite of atorvastatin. The study [1 ] found that in patients with coronary artery disease after coronary stenting vessels atorvastatin unlike pravastatin significantly reduced the antiplatelet effect of clopidogrel.

Since 2004 it was published a series of works that deny the existence of interaction between atorvastatin and clopidogrel. An analysis of data from CREDO study also found no differences in the endpoints in the group of subjects receiving statins and clopidogrel. It was more frequently incidens of myonecrosis after  stenting [30 ] in patients receiving  the combination of clopidogrel with atorvastatin or simvastatin than in patients treated with pravastatin or fluvastatin (41.6 versus 8% , P = 0.004). The results are probably due to the mutual "weakening" effects of clopidogrel and statin because of competing interactions at the level CYP3A4.

The drug has no effect on the pharmacokinetic characteristics of angiotensin-converting factor ( ACF ), blockers  of angiotensin receptor II,  aspirin, warfarin, digoxin [34, 44].

Fluvastatin. It is an active drug, metabolized by CYP2C9. The result is two active metabolites. Inhibiting activity of 5- hydroxyfluvastatin to HMG -CoA reductase is 85 % of the activity of fluvastatin, and of 6 - hydroxyfluvastatin is 45% [ 52].

On the pharmacokinetics of fluvastatin do not affect inhibitors of CYP3A4 but fluconazole, which inhibits not only CYP3A4 but CYPC9 increases the maximum concentration and prolongs the half-life of fluvastatin. In general, the potential ability of fluvastatin to engage in drug interactions are  lower than in substrates of CYP3A4. In the literature there are no data on the development of myopathy or rhabdomyolysis during concomitant use with other drugs [37 ]. A data FDA has 2 messages of rhabdomyolysis in patients receiving concomitant fluvastatin plus fibrates [51 ].

Pravastatin. It is an active drug. It has not biotransformation and active decreed in bile invariably. Inhibitors of CYP3A4, CYP2C9, CYP2D6 not alter the pharmacokinetics of pravastatin, thus these combinations are safe. Absorbed by hepatocytes with OATP-C. Hemfybrozyl inhibits OATP-C and increases the maximum concentration and AUC of pravastatin and  the risk of adverse medical events [52].

It has been reported about increase of bioavailability of pravastatin of 5-23-fold in patients receiving concomitant pravastatin plus cyclosporine. It is confirmed the increased risk of myopathy in patients receiving concomitant pravastatin  with cyclosporine [36, 39].

Rosuvastatin. It is an active drug. " Absorbed " by hepatocytes involving OATP -C. About 10 % of the drug is metabolized by CYP2C9 in hepatocytes and   by CYP2C19. 90% of rosuvastatin excreted in bile [6, 55]. Gemfibrozil inhibits OATP - C and increases the maximum concentration of rosuvastatin of 2 -fold, and the risk of1 adverse effects [ 46]. Rosuvastatin is metabolized to a small degree by CYP2C9 and fluconazole no significantly increases the maximum concentration and AUC of rosuvastatin in plasma [9 ].

Thus, statins are highly active for the treatment of dyslipidemia and prevention of cardiovascular diseases. Statins are generally well tolerated, some members of the class of statins have pharmacological differences, allowing differentiated approach to their choice. Prescribing a statin possible interactions with other drugs deserve particular attention.

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