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Eur J Clin Pharmacol (2001) 57: 357±364 DOI 10.1007/s002280100329 R EV IE W A RT I C L E M. Igel á T. Sudhop á K.vonBergmann Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins) Received: 26 February 2001 / Accepted in revised form: 23 May 2001 / Published online: 13 July 2001 Ó Springer-Verlag 2001 Abstract 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins) are mainly considered for long-term use and often constitute part of a multiple-drug regime. Besides common adverse drug eects, such as nausea, abdominal discomfort and headaches, all statins harbour the risk of myopathy and fatal rhabdomyolysis. Usually, the frequency of myopathy is low but the incidence increases during concomitant drug therapy. Statins do not dier in their pharmacodynamic property. Therefore, the dierences in their pharmacokinetic pro®les, i.e. anity for metabolising enzymes, constitute the rationale for choosing a speci®c statin especially for combination therapy. In order to point out harmful combinations of therapeutics, this review summarises the pharmacokinetic data of six clinically used statins (atorvastatin, cerivastatin, ¯uvastatin, lovastatin, pravastatin and simvastatin) with special regard to metabolism and drug interactions. In summary, statins that lack a signi®cant hepatic metabolism, i.e. pravastatin, or that are metabolised by more than one cytochrome P450 isoenzyme, i.e. ¯uvastatin, or whose metabolism is taken over by other cytochrome P450 isoenzymes in case of blockage of the main metabolising enzyme, i.e. cerivastatin, are the least prone to drug interactions. Nevertheless, in case of a speci®c concomitant drug therapy known to be associated with a higher risk of adverse events, i.e. cyclosporin A and statin, clinical symptoms of myopathy and biochemical data, such as increasing serum creatine phosphokinase, should be monitored carefully. Keywords HMG-CoA-reductase inhibitor á Statin á Pharmacokinetic M. Igel á T. Sudhop á K. von Bergmann (&) Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany E-mail: [email protected] Tel.: +49-228-2876080 Fax: +49-228-2876094 Introduction 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors (statins) represent the most ecient drugs for the treatment of hypercholesterolaemia. Plasma cholesterol is lowered due to the inhibition of endogenous cholesterol synthesis and the subsequent increased expression of the low-density lipoprotein (LDL) receptor, resulting in an upregulated catabolic rate for plasma LDL. In primary and secondary prevention studies the incidence of coronary heart disease and mortality was signi®cantly reduced [1, 2, 3, 4, 5]. Although these drugs are generally well tolerated, adverse events are associated with their short- and long-term use and especially with concomitant therapy leading to myopathy and potentially fatal rhabdomyolysis [6, 7, 8, 9, 10, 11]. Since the prevalence of adverse events varies among the statins and since pharmacokinetic considerations may explain these differences only in part, it is the aim of this review to summarise the pharmacokinetic properties of statins and to emphasise their clinically important drug interactions. Overview of basic pharmacokinetic properties of statins Six statins ± lovastatin, simvastatin, pravastatin, ¯uvastatin, atorvastatin and cerivastatin ± are currently used (Table 1). Lovastatin, simvastatin and pravastatin are derived from Aspergillus terreus. Whereas lovastatin is the natural product, the other two are produced by semi-synthetic processes [12, 13, 14]. Fluvastatin, atorvastatin and cerivastatin are completely synthetic compounds. Simvastatin is the butyrate analogue of lovastatin, and is ± like lovastatin ± a prodrug (lactone), whereas the other statins are administered as active compounds (acid). Pravastatin is the most hydrophilic compound. Cerivastatin and ¯uvastatin are almost completely absorbed after oral administration, whereas the low extent of absorption of pravastatin is probably CYP2C8 CYP2C9 CYP2D6 CYP3A4 Metabolites contributing to lipid-lowering eect tmax (h) Terminal half-life (h) Clearance (l/h/kg) Protein binding (%) Hepatic extraction (% absorbed dose) CYP substrate Origin Prodrug (Lactone) Lipophilicity, C log P (octanol/water) Crosses blood±brain barrier Dosage Absorption (%) Bioavailability (%) Eect of food on bioavailability Yes [20, 38, 75, 81, 92, 93] (+) (+) + Yes [81] Yes [21, 29, 75] (+) (+) + Yes [99] 5±80 mg 60±85% [77] <5% [7] No [7] 10±80 mg 31% [6] <5% [6] Yes (50% increase) [69] 1.3±2.4 [7] 1.9±15.6 [69] 0.45 [20] 95% [7, 90] 78±87 [20] Lactone [76] Lactone [76] 2.8 [81] 2.5±15 [79] 0.26±1.1 [20] 95% [6] >70% [20] Semi-synthetic [13] Yes 4.7 (47,860) Simvastatin Microbial [12] Yes [69] 4.3 (18,620) [20] Lovastatin (+) Yes, mainly inactive [25, 26] (+) Clinically not relevant [21, 38, 94, 95, 96, 97] 0.9±1.6 [78, 88] 0.8±3.0 [81] 0.81 [20] 48% [25] 66% [25] 5±40 mg 35% [78] 17% [78] Yes (30% decrease) [69, 84] No [76] Semi-synthetic [11] No ±0.2 (0.6) Pravastatin + (+) (+) Yes, mainly inactive [98] Yes [21, 35, 75, 98] 0.5±1.5 [79] 0.5±2.3 [9] 0.97 [79] >99% [79, 91] 68 [69] 20±80 mg 98% [14] 10±35% [81] Yes (15±25% decrease) [69, 85, 86] No [69] Synthetic [14] No 3.2 (1738) Fluvastatin + Active [10, 20, 69] Yes [75] 2±4 [69] 11±30 [80, 89] 0.25 [20] >98% [10] >70 [20] 10±80 mg 30% [80] 12% [10] Yes (13% decrease) [20, 69] N/a Synthetic [10] No 4.1 (1482) Atorvastatin + Active [27] + Yes [36, 39, 75] 0.1±0.8 mg >98 [15] 60% [27, 82, 83] Morning: Yes (23% decrease) [69]; Evening: No [15, 87] 2.5±3.0 [82, 83] 2±3 [27, 83] 0.2 [27] >99% [27, 83] N/a N/a Synthetic [11] No 1.5 (29.5) Cerivastatin Table 1 Pharmacokinetic data of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). N/a not available, tmax time to reach peak plasma concentration, CYP cytochrome P450, C log P logarithm of the partition coecient based on octanol/water phase 358 359 due to its hydrophilicity and consequently low intestinal permeability. The low intestinal uptake of lovastatin is probably related to its hydrophobic properties, which prevent complete dissolution in the intestinal ¯uid. Concomitant food intake does not aect the absorption of simvastatin and cerivastatin, at least not when low-fat meals are consumed [7, 15]. The diurnal variation of cholesterol synthesis leads to the recommendation that statins when administered only once a day should be taken at night [16]. Daily dosage ranges vary from 0.1 mg to 80 mg and the following doses have been proposed to be approximately equipotent: 10 mg atorvastatin, 20 mg simvastatin, 40 mg lovastatin, 40 mg pravastatin, 80 mg ¯uvastatin and 0.4 mg cerivastatin. These dose regimens lead to an approximately 22% reduction in total cholesterol and approximately 27% reduction in LDL cholesterol [17]. Dose±response studies revealed a non-linear relationship and most of the eectiveness is preserved at low doses, although higher doses may further reduce LDL cholesterol. As a rule of thumb, a doubling of the dose causes a lowering of the cholesterol of about a further 5% in total and 7% of LDL cholesterol [17]. cerivastatin can also be metabolised by CYP2C8 [20, 36]. Another property predicting drug interaction is the anity of binding to cytochrome enzymes. Fluvastatin shows high anity to CYP2C9, lovastatin and simvastatin exert moderate anity to CYP3A4 and cerivastatin has the lowest anity to CYP3A4 [21]. Therefore, ¯uvastatin is hardly displaced from CYP2C9, for example, by diclofenac, a typical substrate of CYP2C9 with lower binding anity. In contrast, the metabolism of lovastatin and simvastatin may be more easily disturbed by substrates of the same iso-enzyme, i.e. azole antifungals such as itraconazole [37, 38]. Finally, when transformation of cerivastatin by CYP3A4 is blocked, metabolism is performed by CYP2C8 [33, 39]. All in all, the available data clearly indicate that biotransformation by microsomal cytochrome enzymes is the predominant metabolic pathway in ®ve of six statins. Induction or inhibition of cytochrome isoenzymes often accounts for drug interactions and the majority of clinically used drugs interact with CYP. This information may in¯uence the choice of drugs considered for combination therapy. Metabolism Drug interactions Lovastatin and simvastatin are administered as lactone prodrugs and, consequently, they are activated by hydrolysis to their correspondent hydroxyl acids by nonspeci®c carboxyesterase in the intestinal wall, liver and to some extent in plasma. Therefore, variations in carboxyesterase activity might in¯uence the individual response to these statins [18]. Due to their rapid metabolism in gut and liver, the systemic bioavailability is relatively low, but does not correspond with their biological activity, since their main site of action is in the hepatocyte. Concerning drug interactions, the metabolism by cytochrome P450 enzymes (CYP) seems to be the most important [19, 20, 21]. These enzymes are expressed mainly in liver microsomes and in gut wall [22]. The CYP3A iso-enzymes are the most abundant and account for approximately 30% in liver and 80% in small intestinal mucosa [23]. In addition to CYP3A4, three distinct cytochromes, CYP2C8, CYP2C9 and CYP2D6, play an important role in the metabolism of statins. With the exception of pravastatin, all statins undergo extensive microsomal metabolism by CYP enzymes. Pravastatin is transformed enzymatically in the liver cytosol [20, 24, 25, 26]. CYP3A species, especially CYP3A4, are the major enzymes metabolising the lactone form of lovastatin and simvastatin. Atorvastatin and cerivastatin are also primarily transformed by CYP3A4 [27, 28, 29, 30, 31, 32, 33]. CYP2C9 is the major enzyme metabolising ¯uvastatin, whereas CYP3A4, CYP2C8 and CYP2D6 may also transform ¯uvastatin, albeit to a lesser extent [34, 35]. Similarly, Drug interactions with statins are described, for example, for the immunosuppressants cyclosporin A [40, 41, 42, 43, 44, 45, 46] and tacrolimus [47, 48, 49, 50], for azole antifungals such as itraconazole, ketoconazole and ¯uconazole [38, 51, 52, 53, 54, 55], for macrolide antibiotics such as eythromycin [56, 57, 58], for lipid lowering ®brates such as gem®brozil [57, 59, 60, 61, 62, 63, 64, 65], for nicotinic acid derivatives [41, 57, 66, 67], for protease inhibitors [19], for the anticoagulant warfarin [21, 68] and for digoxin [57]. Pathophysiology Skeletal muscle toxicity is the predominant serious adverse event following statin treatment [69, 70]. Myopathy is a rare, but severe, side eect de®ned by myalgia or weakness and a more than tenfold increase in creatine phosphokinase activity [71]. Mevalonic acid formation is inhibited in striated muscle. Subsequently, there is a lack of cholesterol precursors produced from mevalonic acid. These are important for several cell functions and serve, for example, glycosylation of cell surface proteins, electron transfer during mitochondrial membranes and post-translational modi®cation of regulatory proteins [72]. Myopathy can progress to rhabdomyolysis which ®nally may result in renal failure. The incidence of myopathy or rhabdomyolysis is dose dependent and interference with statin metabolism is the most likely mechanism to increase their plasma concentrations. 360 Immunosuppressants Cyclosporin A and tacrolimus are metabolised in the liver and small intestine by CYP3A4. Therefore, the likelihood of drug interaction caused by concomitant statin treatment can be divided into four dierent groups: 1. Lovastatin, simvastatin, atorvastatin: as they are solely transformed by CYP3A4, they bear the highest risk of skeletal muscle toxicity. 2. Cerivastatin: due to low binding anity to CYP3A4 and alternative metabolism by CYP2C8, the risk of myotoxicity is lower than in group 1. 3. Fluvastatin: more than 90% is biotransformed by CYP2C9. Despite a small increase in ¯uvastatin plasma concentrations following concomitant therapy with cyclosporin A, myotoxicity has not been reported. 4. Pravastatin: most of the drug is eliminated unchanged and derivatives in plasma or urine are generated mainly by phase-II metabolism and degradation. Inhibition of CYP3A4 does not signi®cantly increase plasma concentrations. Nevertheless, an increased pravastatin area under the plasma concentration±time curve (AUC, 5- to 23-fold) has been reported [73, 74] and the underlying mechanism is believed to be on the level of biliary secretion. However, interactions with cyclosporin A have not been reported [57]. Azole antifungals Itraconazole, ketoconazole and ¯uconazole are strong inhibitors of CYP3A. Therefore, combination therapy should be performed with either ¯uvastatin or pravastatin. Macrolide antibiotics Eythromycin and clarithromycin are weak inhibitors of CYP3A isoenzymes. Nevertheless, cases of increased bioavailability of statins as well as cases of myositis and rhabdomyolysis have been reported with concurrent use of lovastatin and simvastatin. As data concerning atorvastatin and cerivastatin are not available, these drugs are also not recommended for combination therapy. Fibrates Interactions between statins and ®bric acid derivatives, such as gem®brozil, deserve particular attention as myopathy can occur with either drug alone. Liver function can be impaired by ®brates resulting in diminished hepatic clearance of statins and, consequently, higher plasma levels of statins. Therefore, patients with impaired liver function should not receive combination therapy. Furthermore, ®brates are primarily excreted renally, and renal impairment may increase the risk of myopathy. Recently, the eect of gem®brozil on the pharmacokinetics of simvastatin was investigated and revealed that gem®brozil increases the plasma concentration of active simvastatin acid without inhibiting CYP3A4 [65]. Thus, the interactions seem to be pharmacodynamic and pharmacokinetic in nature and, unfortunately, have been reported with each statin. Especially when co-administered with cerivastatin, gem®brozil seems to induce more myopathic interactions than other ®brates. Thus, concomitant use of gem®brozil and cerivastatin is not recommended [100]. However, there is no pharmacokinetic interaction between cerivastatin and feno®brate [27]. Nicotinic acid derivatives The mechanism behind the interaction of nicotinic acid and lovastatin is not completely understood, but myopathy has been reported in 2% of patients receiving this combination. Possibly, the depletion of cholesterol might destabilise sarcolemmic membranes and increase membrane ¯uidity. Elevated plasma concentrations of lovastatin are not reported. No interactions have been observed when nicotinic acid derivatives were administered with simvastatin, pravastatin or ¯uvastatin. Coumarin anticoagulants Although the mechanism of interaction between warfarin and statins is uncertain, reduction of warfarin dosage is sometimes required to achieve an appropriate level of anticoagulation. Warfarin is a racemic compound and metabolism of the (S)-enantiomer is primarily catalysed by CYP2C9, while (R)-warfarin undergoes transformation primarily by CYP3A4. Given that these two isoenzymes are involved in metabolism, competition with lovastatin, simvastatin, cerivastatin, atorvastatin and ¯uvastatin may be a contributing factor. The anticoagulant eects of warfarin are not known to be altered by pravastatin. Calcium-channel antagonists and digoxin Diltiazem and verapamil are weak inhibitors of CYP3A4 and statins metabolised mainly by this enzyme should therefore be avoided. Mibefradil, a calciumchannel antagonist, strongly suppressed, at therapeutically relevant concentrations, the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory eects on CYP3A4/5, while the eects of mibefradil on ¯uvastatin, 361 a substrate for CYP2C8/9, in this system were minimal. Since mibefradil was a potent mechanism-based inhibitor of CYP3A4/5, it was anticipated that clinically signi®cant drug±drug interactions would likely ensue when mibefradil was co-administered with agents that are cleared primarily by CYP3A-mediated pathways [75]. This is the probable reason for withdrawal of this calcium-channel blocker from the market. The only likely clinical interaction between statins and digoxin is for simvastatin, which caused slight elevation in plasma digoxin concentrations. for early symptoms of myopathy, administration of statins and potentially interfering drugs at least 3 h apart, choice of statin with accordant pharmacokinetic pro®le for concomitant therapy. In contrast, pravastatin is water-soluble and does not undergo metabolism via CYP to any signi®cant extent. In patients receiving complex pharmacotherapy, pravastatin would be a good choice due to its lack of signi®cant hepatic metabolism and consequent lack of clinically signi®cant drug±drug interactions. However, the above-mentioned strategies should also be followed. Protease inhibitors Acknowledgement Supported by a grant from the Bundesministerium fuÈr Bildung, Forschung, Wissenschaft und Technologie (01EC9402). The protease inhibitors indinavir, nel®navir, ritonavir and saquinavir are substrates and inhibitors of CYP3A4. In addition, ritonavir is also a signi®cant inhibitor of CYP2D6. Concomitant administration of ritonavir and lovastatin increases the AUC of lovastatin threefold. Therefore, giving statins with inhibitory potential for CYP3A4 and/or CYP2D6 should be avoided or dosage of statins should be reduced to avoid the potential for rhabdomyolysis. Although little information is available, pravastatin is to be preferred and cerivastatin might be a second-line choice due to compensatory metabolism by CYP2C8. Nutritional products Grapefruit juice increases the oral bioavailability of several drugs known to be metabolised by CYP3A4. The underlying mechanism is a furanocoumarin (dihydroxybergamottin, DHB) present in grapefruit juice that causes inactivation of CYP3A4 and subsequent accelerated degradation of the enzyme. As the amount of DHB varies greatly between dierent brands, the result does not have the predictability to allow a safe and effective reduction in the dose of statin. Thus, those statins metabolised mainly by CYP3A4 should not be taken together with grapefruit juice. Conclusion Pharmacokinetic drug±drug interactions in¯uencing drug ecacy, tolerability and compliance are both common and of more clinical relevance than often anticipated. 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