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Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: Drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions

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Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hypercholesterolemia. Their efficacy in preventing cardiovascular events has been shown by a large number of clinical trials. However, myotoxic side effects, sometimes severe, including myopathy or rhabdomyolysis, are associated with the use of statins. In some cases, such toxicity is associated with pharmacokinetic alterations. In this review, the pharmacokinetic aspects and physicochemical properties of statins are reviewed in order to understand the mechanism governing their pharmacokinetic alterations. Among the statins, simvastatin, lovastatin and atorvastatin are metabolized by cytochrome P450 3A4 (CYP3A4) while fluvastatin is metabolized by CYP2C9. Cerivastatin is subjected to 2 metabolic pathways mediated by CYP2C8 and 3A4. Pravastatin, rosuvastatin and pitavastatin undergo little metabolism. Their plasma clearances are governed by the transporters involved in the hepatic uptake and biliary excretion. Also for other statins, which are orally administered as open acid forms (i.e. fluvastatin, cerivastatin and atorvastatin), hepatic uptake transporter(s) play important roles in their clearances. Based on such information, pharmacokinetic alterations of statins can be predicted following coadministration of other drugs or in patients with lowered activities in drug metabolism and/or transport. We also present a quantitative analysis of the effect of some factors on the pharmacokinetics of statins based on a physiologically based pharmacokinetic model. To avoid a pharmacokinetic alteration, we need to have information about the metabolizing enzyme(s) and transporter(s) involved in the pharmacokinetics of statins and, along with such information, model-based prediction is also useful.

Introduction

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) inhibit the synthesis of mevalonate, a rate-limiting step in cholesterol biosynthesis, leading to a reduction in the plasma low density lipoprotein (LDL)-cholesterol level. High plasma LDL-cholesterol is a risk factor of cardiovascular diseases and, therefore, cholesterol-lowering drugs are used to prevent them. Some randomized controlled trials have shown that statins have potent cholesterol-lowering effects and reduce the risk of cardiovascular diseases in everyday medical practice (Scandinavian Simvastatin Survival Study Group, 1994, Shepherd et al., 1995, Sacks et al., 1996, Bertolini et al., 1997, The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, 1998). On the other hand, some of statins exhibit a number of adverse effects, such as myopathy or rhabdomyolysis (Staffa et al., 2002, Thompson et al., 2003). Concomitant use of other drugs sometimes increases the risk of severe myotoxicity (Pierce et al., 1990, Pogson et al., 1999). Cerivastatin causes a serious myotoxicity, which has resulted in 31 deaths in the USA (Staffa et al., 2002). Among these patients, 12 were concomitantly taking gemfibrozil, suggesting that combination therapy with these drugs might increase the risk of side effects due to a drug–drug interaction (Staffa et al., 2002). Indeed, the plasma concentration of cerivastatin was reported to be increased by coadministration of gemfibrozil (Backman et al., 2002). Due to this severe side effect, cerivastatin was voluntarily withdrawn from the market in 2001. This review will summarize the mechanism of drug–drug interactions between statins and other drugs, using comparisons of the characteristics of statins, their physicochemical properties, elimination routes, and so on.

Mevastatin, a lead compound of the statins, is a fungal product, initially extracted from Penicillium citrinum (Endo et al., 1976). Lovastatin, simvastatin and pravastatin are also derivatives of fungal products (Alberts et al., 1980, Hoffman et al., 1986, Endo, 1992). Among them, lovastatin and simvastatin possess a lactone ring in their structure and are transformed into the active open acid form in the body while pravastatin is administered as the biologically active open acid form (Fig. 1). On the other hand, fluvastatin is a completely synthetic statin with a very different structure from the statins derived from fungal products (Fig. 1). Fluvastatin is a mevalonolactone derivative with a fluorophenyl-substituted indole ring (Fig. 1). Statins, which reached the market after fluvastatin, also have similar structures with fluorophenyl groups. All of the totally synthetic statins have open acid forms. Depending upon their chemical structures, they have different affinities for HMG-CoA reductase, which determines their pharmacological effects, and different pharmacokinetic properties (i.e. tissue distribution, metabolic stability, enzymes and transporters involved in their metabolism, etc.). Thus, the information on the physicochemical properties of statins is useful to understand their pharmacokinetic properties. Drugs which interact with statins depend upon the pharmacokinetic properties of each of statins.

Recently, some reports on genetic polymorphisms in drug metabolizing enzymes and transporters have been published and interindividual differences in the pharmacokinetics of statins associated with them have been reported (Kirchheiner et al., 2003, Nishizato et al., 2003, Kajinami et al., 2004a, Niemi et al., 2004, Wang et al., 2005). This review also summarizes the information on the interindividual differences in pharmacokinetics of statins associated with these genetic factors.

Section snippets

Direct mechanism on 3-hydroxy-3-methylglutaryl coenzyme A reductase

All statins currently on the market possess a HMG-like moiety (Fig. 1): simvastatin and lovastatin have a lactone ring instead of this moiety and are transformed into the biologically active form with an open acid in the body while other newer statins are administered as the open acid forms. Newer statins with HMG-moieties have a higher affinity for HMG-CoA reductase and exert more potent inhibitory effects (Istvan & Deisenhofer, 2001, McTaggart et al., 2001, Holdgate et al., 2003). Enzyme

The characteristics of statins

Statins have different pharmacokinetic profiles that are associated with their physicochemical properties. Table 3 shows the logD values reflecting the lipophilicity of statins. Simvastatin and lovastatin, which are administered as prodrugs with a lactone ring, have high logD values while other statins with open acid structures are less lipophilic. Among them, the logD of pravastatin is the lowest. Generally, compounds with high logD values can easily cross lipid bilayer membranes by passive

Model analysis of pharmacokinetic alterations of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

In Section 3, some factors affecting the pharmacokinetics of statins were reviewed. In this section, we present some quantitative analyses of the effects of these factors (i.e. the increase or decrease in metabolic or transport rates) based on a physiological model. A physiological model based analysis is useful for the quantitative estimation of the impact of these factors on the plasma concentration or AUC. Here, we have carried out an analysis based on a physiological model as shown in Fig. 9

OATP1B1 inhibitor

Among OATP1B1 inhibitors, there are only a few drugs which may cause a drug–drug interaction with coadministered drugs in clinical situations because of the lower therapeutic concentrations compared with Ki (Shitara et al., 2005). Among them, cyclosporin A (CsA) is one of the drugs which may affect the pharmacokinetics of other drugs by the inhibition of OATP1B1-mediated hepatic uptake. In addition, CsA also affects CYP3A4 and P-gp as well as OATP1B1. CsA affects the plasma concentrations of

OATP1B1

There have already been some reports of pharmacokinetic alterations of statins associated with the genetic polymorphism of OATP1B1 (Nishizato et al., 2003, Iwai et al., 2004, Morimoto et al., 2004, Mwinyi et al., 2004, Niemi et al., 2004, Tachibana-Iimori et al., 2004). Fig. 15 shows the reported genetic polymorphisms of this transporter and Table 13 shows the allelic frequencies of the variants found in the OATP1B1 gene (Tirona et al., 2001, Nozawa et al., 2002, Nishizato et al., 2003, Niemi

Conclusion

In this review, we have described the pharmacokinetic properties and physicochemical features of the statins. In addition, we have performed a model-based analysis and shown how sensitively the pharmacokinetic alterations are caused by a change in the metabolizing enzymes and/or transporters. In the case of combination therapy with statins, their elimination pathways and mechanism, which includes the metabolizing enzyme(s) and transporter(s) involved in their elimination, need to be known in

Acknowledgment

We thank Dr. Hitoshi Sato at Showa University and Dr. Toshiharu Horie at Chiba University for their fruitful advices. We also thank Dr. Hideki Fujino at Kowa Co. Ltd. and Dr. Toshihiko Ikeda at Sankyo Co. Ltd. for their critical reviewing of this manuscript. We are also grateful for Ms. Maiko Kawakami-Takada and Dr. Hiroyuki Kusuhara at the University of Tokyo for performing the uptake studies of statins into rat jejunum everted sacs. All simulation analyses were performed using WinNonlin

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