Metabolism and Drug Interactions of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Transplant Patients

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88) inhibitors are the most effective drugs to lower cholesterol in transplant patients. However, immunosuppressants and several other drugs used after organ transplantation are cytochrome P4503A (CYP3A, EC 1.14.14.1) substrates. Pharmacokinetic interaction with some of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, specifically lovastatin and simvastatin, leads to an increased incidence of muscle skeletal toxicity in transplant patients. It is our objective to review the role of drug metabolism and drug interactions of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin. In the treatment of transplant patients, from a drug interaction perspective, pravastatin, which is not significantly metabolized by CYP enzymes, and fluvastatin, presumably a CYP2C9 substrate, compare favorably with the other statins for which the major metabolic pathways are catalyzed by CYP3A.

Introduction

Hypercholesterolemia is a well-established risk factor for atherosclerosis, leading to cardio-, cerebro-, and peripheral vascular morbidity and mortality Anderson et al. 1987, Castelli et al. 1986, Kannel et al. 1971. With the refinement of immunosuppressive regimens over the last two decades and the reduction of graft loss due to acute and chronic rejection (Schweitzer et al., 1991), accelerated atherosclerosis has become a critical factor in the long-term survival of kidney and cardiac transplant patients Kasiske 1988, Eich et al. 1991, Sharples et al. 1991. In fact, cardiac complications are the most common causes of death in kidney Braun 1990, Florijn et al. 1994, Mahony 1989, Raine et al. 1991, West et al. 1996 and heart (McAllister et al., 1996) transplant patients. Coronary artery disease is present in most heart transplant patients (McAllister et al., 1996). Atherosclerotic lesions often manifest upon the pre-injured vascular epithelium of the transplant organ Hosenpud et al. 1992, Fujita et al. 1993 and, paradoxically, death is frequently the first sign of coronary artery disease in these cardiac transplant patients since ischemic lesions in the denervated, transplanted organ are often asymptomatic (Becker et al., 1988).

Lipid-lowering therapy seems to be useful in primary prevention in renal and cardiac transplant patients without cardiovascular disease, and is mandatory as secondary prevention in those with established coronary artery disease (Wanner et al., 1995). The rationale for treatment of hypercholesterolemia in transplant patients is based upon the likelihood that effective control of serum lipids and lipoproteins results in a beneficial reduction of morbidity and absolute mortality, as demonstrated for nontransplant patients The Scandinavian Simvastatin Survival Study Group 1994, West of Scotland Coronary Prevention Study Group 1995. However, the benefit of lipid-lowering therapy in organ transplant patients has not been statistically proven yet (Bumgardner et al., 1995).

In the past, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.88) inhibitors have emerged as the most valuable drugs to improve lipid profiles in transplant patients Markell et al. 1994, Wanner et al. 1995. In addition to patient survival, studies have also demonstrated an improvement of graft survival and a lower incidence of rejection in patients treated with pravastatin, possibly because of the potentiation of immunosuppressive activity by this agent Katznelson et al. 1996, Kobashigawa et al. 1995. This area has been reviewed recently (Motomura et al., 1997).

In humans, biosynthesis of cholesterol from acetyl-CoA in the liver accounts for 60–70% of the total cholesterol pool, making inhibition of the synthetic pathway an effective target for lipid-lowering therapy. Cholesterol, from either exogenous sources or from endogenous synthesis, is used in the body as an integral component of cellular membranes and for the biosynthesis of steroid hormones, bile acids, and vitamin D Dietschy and Wilson 1970a, Dietschy and Wilson 1970b, Dietschy and Wilson 1970c. In cholesterol synthesis, the conversion of HMG-CoA to mevalonic acid is the rate-limiting step Dietschy and Wilson 1970a, Dietschy and Wilson 1970b, Dietschy and Wilson 1970c. HMG-CoA reductase inhibitors contain a mevalonic acid-like moiety that inhibits HMG-CoA reductase activity by product inhibition (Alberts et al., 1980). In humans, enzyme inhibition results not only in a significant reduction of circulating low-density lipoprotein (LDL) cholesterol, as well as total cholesterol concentrations Grundy and Vega 1985, Hoeg and Brewer 1987, but also in an intermittent increase of high-density lipoproteins (HDLs) (Ahnadi et al., 1993) and a reduction of blood triglyceride concentrations. HMG-CoA reductase is widely distributed in tissues and is regulated by the LDL receptor system Dietschy and Wilson 1970a, Dietschy and Wilson 1970b, Dietschy and Wilson 1970c, Brown and Goldstein 1986.

A reduction of intracellular cholesterol concentrations promotes LDL receptor expression on the hepatocyte surface Bilheimer et al. 1983, Gaddi et al. 1991, and results in an increased extraction of LDL cholesterol from blood. As an additional cholesterol-lowering mechanism, HMG-CoA reductase inhibitors decrease blood concentrations of very low-density lipoproteins (VLDLs) by inhibiting their synthesis and promoting their catabolism Grundy 1988, Slater and MacDonald 1988. VLDL is a precursor of LDL, and inhibition of its production results in lower LDL blood concentrations, as well as lower triglyceride blood concentrations. HMG-CoA reductase inhibitors reduce synthesis of VLDLs in the liver by inhibiting formation of cholesterol, which is required for the production of VLDL, and by decreasing apolipoprotein B, the major apolipoprotein in LDL, secretion from the liver (Thompson et al., 1996). The increased number and activity of LDL receptors that recognize apolipoproteins B and E leads to an increased clearance of VLDL and their remnants (Gaw et al., 1993). HMG-CoA reductase inhibitors also increase intracellular, LDL receptor-independent VLDL metabolism (Sehayek et al., 1994). Other antiatherogenic effects of HMG-CoA reductase inhibitors include a 10% reduction of plasma viscosity and decreased platelet aggregation Koppensteiner et al. 1990, Lea and McTavish 1997, Martinez et al. 1996, Mayer et al. 1992. It has also been postulated that these drugs may produce a relaxing effect on smooth muscle that could potentially result in a reduction of blood pressure (Escobales et al., 1996), and there is some evidence that HMG-CoA reductase inhibitors partially reverse vascular hyper-reactivity Anderson et al. 1995, Treasure et al. 1995 associated with hypercholesterolemia Seiler et al. 1993, Vita et al. 1990. It remains unclear as to whether the inhibition of proliferation and migration of vascular smooth muscle cells produced by several HMG-CoA reductase inhibitors is a clinically desirable effect Vaughan et al. 1996, Corsini et al. 1992, Weissberg et al. 1996.

In the long term, HMG-CoA reductase inhibitors slow the progression or even cause regression of coronary atherosclerosis, resulting in fewer new lesions and total occlusions compared with untreated hypercholesterolemic patients MAAS Investigators 1994, Jukema et al. 1995. As a possible mechanism, it has been proposed that lipid-lowering therapy shrinks the lipid cores of atherosclerotic plaques, thus avoiding plaque rupture that triggers intramural hemorrhage and intraluminal thrombosis Davies et al. 1991, Pedersen and Tobert 1996, Vos et al. 1993.

The chemical structures of the six HMG-CoA reductase inhibitors currently approved for use in the United States—lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin—are shown in Fig. 1. Lovastatin, simvastatin, and pravastatin are derived from the fungus Aspergillus terreus Alberts et al. 1980, Hoffman et al. 1986. Whereas lovastatin is a natural product, simvastatin and pravastatin are produced by semi-synthetic processes. Simvastatin is the 2,2-dimethyl butyrate analogue of lovastatin, and like lovastatin, is a prodrug. Pravastatin is produced by microbial transformation of mevastatin, the first HMG-CoA reductase inhibitor isolated (Endo et al., 1976), and is hydroxylated in the 6′-position of its decalin ring by a soluble cytochrome P450 (CYP) enzyme Arai et al. 1988, McTavish and Sorkin 1992. In contrast to lovastatin and simvastatin, pravastatin is administered as the sodium salt of the active acid (McTavish and Sorkin, 1992). Fluvastatin, atorvastatin, and cerivastatin (Fig. 1B) are totally synthetic molecules and have structures distinct from the fungi-derived HMG-CoA reductase inhibitors. The fluorophenyl indole moiety of fluvastatin mimics coenzyme A, as it would interact with HMG-CoA reductase and its side chain mevalonate Blum 1994, Kathalawa 1991. All three synthetic HMG-CoA reductase inhibitors are administered as active compounds.

The physical and chemical properties of HMG-CoA reductase inhibitors recently have been compared by Lennernäs and Fager (1997). The HMG-CoA reductase inhibitors have a widely differing solubility in water Serajuddin et al. 1991, Lennernäs and Fager 1997. Pravastatin is more hydrophilic than fluvastatin, and fluvastatin is more hydrophilic than the other HMG-CoA reductase inhibitors, thus resulting in different pharmacokinetic characteristics (Lennernäs and Fager, 1997) and tissue distribution patterns (Sirtori, 1993). On a milligram/kilogram basis, cerivastatin is the most potent HMG-CoA reductase inhibitor, with usual doses in the range of 100–300 μg/day. In enzyme inhibition tests based on the native ribosomal fraction isolated from rat liver, the IC₅₀ of cerivastatin was 1.1 · 10⁻⁹ mol · L⁻¹ (Bischoff et al., 1997). In comparison, in the same assay, the IC₅₀ values of simvastatin, lovastatin, and pravastatin were 66 · 10⁻⁹ mol · L⁻¹, 77 · 10⁻⁹ mol · L⁻¹, and 176 · 10⁻⁹ mol · L⁻¹, respectively. In patients, the following doses have been proposed to be approximately equipotent: 5-mg simvastatin ≅ 15-mg lovastatin ≅ 15-mg pravastatin ≅ 40-mg fluvastatin (Pedersen and Tobert, 1996). Clinical studies indicated that atorvastatin has a potency and efficacy close to or higher than simvastatin Dart et al. 1997, Lea and McTavish 1997. Within the recommended dosage ranges, the relationship between response, expressed as percent reduction in LDL cholesterol, and dose is log-linear (Pedersen and Tobert, 1996). In large comparative trials, the dose-response lines for all HMG-CoA reductase inhibitors were generally parallel. The slope was such that each doubling of the dose yielded an additional mean reduction of LDL cholesterol concentrations of approximately 6% (Pedersen and Tobert, 1996).

Among patients with hyperlipidemia, transplant patients constitute a distinct subgroup since most of them require life-long treatment with immunosuppressive drugs. The use of HMG-CoA reductase inhibitors, or “statins,” in transplant patients is complicated by the fact that there is an increased incidence of toxicity when these drugs are given in combination with immunosuppressants (Table 1). The most dramatic side effects of these drugs in transplant patients are skeletal muscle toxicities that may cause myopathy and may eventually progress to rhabdomyolysis. Although some of the “statins” share close structural similarity (Fig. 1) and have similar lipid-lowering mechanisms and toxicity profiles, analysis of their pharmacokinetics shows profound mechanistic differences. Based on these differences, it can be hypothesized that specific HMG-CoA reductase inhibitors may have a lower potential of drug interactions with immunosuppressants and, therefore, may have advantages over others in transplant patients. It is our objective to review drug metabolism and drug interaction of statins and their role in the development of myopathy in transplant patients.