Role of multi-drug resistance-associated protein-1 transporter in statin-induced myopathy

Dorajoo, Rajkumar; Pereira, Barry P.; Yu, Zou; Gopalakrishnakone, P.; Leong, Cheng Chee; Wee, Aileen; Lee, Edmund

doi:10.1016/j.lfs.2008.01.021

Cited by 14 publications

(10 citation statements)

References 21 publications

(19 reference statements)

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“…Recently, a role for rat Mrp1 in statin-induced myopathy has been suggested in studies that demonstrate precipitation of rosuvastatin-mediated skeletal muscle toxicity in rats cotreated with the MRP inhibitor, probenecid. 59 Interpretation of these findings remains difficult for a number of reasons, including a lack of demonstration that rat Mrp1 transports rosuvastatin, absence of Mrp1 expression data in tissues such as skeletal muscle, and a deficiency of information regarding differences in plasma and tissue concentrations of rosuvastatin after probenecid cotreatment. 59 The dynamic interplay between uptake and efflux transporter activities likely controls muscle fiber statin concentrations, which determines susceptibility to toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…59 Interpretation of these findings remains difficult for a number of reasons, including a lack of demonstration that rat Mrp1 transports rosuvastatin, absence of Mrp1 expression data in tissues such as skeletal muscle, and a deficiency of information regarding differences in plasma and tissue concentrations of rosuvastatin after probenecid cotreatment. 59 The dynamic interplay between uptake and efflux transporter activities likely controls muscle fiber statin concentrations, which determines susceptibility to toxicity. We have shown that the toxicity of rosuvastatin and atorvastatin in primary human skeletal muscle cells is dependent on the achieved intracellular drug concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Knauer

Urquhart

Schwabedissen

et al. 2010

Circulation Research

183

146

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Rationale: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. MG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, statins, are highly effective drugs for the treatment of hypercholesterolemia, a major risk factor of cardiovascular disease. Statins inhibit the synthesis of mevalonate, the rate-limiting step in cholesterol biosynthesis. 1,2 Although statins are generally well tolerated, 3 skeletal muscle side effects are commonly reported among those treated. One such side effect, myalgia, which is defined as muscle aches or weakness in the absence of blood creatine kinase elevation, occurs in 5% to 15% of statin-treated patients. 2,4 -8 In rare cases, potentially life-threatening statin-induced rhabdomyolysis may occur, a condition characterized by acute muscle damage, resulting in pronounced elevation in creatine kinase levels and possible renal failure. 9 The pathophysiology of statin-induced myopathy is not completely understood. The leading mechanism suggests a role for cellular depletion of secondary metabolic intermediates of mevalonate in the development of statin-induced myotoxicity. 10 In addition to decreased cholesterol synthesis, HMG-CoA reductase inhibition by statins causes a commensurate reduction in the levels of downstream metabolic products including isoprenoids, dolichol, and ubiquinone (coenzyme Q10). 10 -13 Among these are the isoprenoid secondary metabolic intermediates geranylgeranylpyrophosphate and farnesylpyrophosphate that are involved in protein isoprenylation and activation of small GTPases such as Rho and Rab. The important role for diminished isoprenylation in the mechanism of statin myotoxicity is related to induction of the muscle atrophy-linked protein atrogin-1. 12 This is highlighted by the findings that supplementation of geranylgeranylpyrophosphate to cultured skeletal myotubes or isolated myofibers treated with statins leads to attenuation of toxicity, 11,13-15 whereas inactivation of a Rab and RhoA induces toxicity. 11,13 Decreased geranylgeranylation of small GT-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Knauer

Urquhart

Schwabedissen

et al. 2010

Circulation Research

183

146

View full text Add to dashboard Cite

show abstract

“…Of the others, based upon a meta-analysis of 18 prospective randomized controlled trials (comprising 71,108 individuals), the highest rate of adverse effects, including greater than 10-fold CK elevations and rhabdomyolysis, was found to be associated with atorvastatin and the lowest risk with fluvastatin, whereas the risks for simvastatin, lovastatin, and pravastatin were intermediate and comparable [15]. Differences in pharmacodynamics and pharmacokinetics may account for these differences and it is noteworthy in this regard that atorvastatin has a much longer plasma elimination half-life (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) …”

Section: Type Of Statinmentioning

confidence: 99%

“…Other drugs reported to interact with statins and to cause rhabdomyolysis include colchicine [18], azithromycin [19], fusidic acid [20], erlotinib [21], and sitagliptin [22]. Increased risk of myotoxicity was reported in mice when rosuvastatin was combined with probenecid, which inhibits the muscle MRP1 statin efflux transporter [23].…”

Section: Drug Interactionsmentioning

confidence: 99%

Update on Toxic Myopathies

Mastaglia

Needham

2011

Curr Neurol Neurosci Rep

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The toxic myopathies are a clinically and pathologically diverse group of disorders that can be caused by a variety of therapeutic agents used in clinical practice, as well as various venoms and other biological toxins. The most important iatrogenic causes are the statin and fibrate cholesterol-lowering agents that can cause a severe necrotizing myopathy and acute rhabdomyolysis and myoglobinuria. The current update focuses on the mechanisms of statin myotoxicity and the importance of genetic predisposing factors for statin myopathy, as well as the recently described form of necrotizing autoimmune myopathy, which is associated with antibodies to the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme and is responsive to aggressive immunotherapy. Mitochondrial myopathies associated with antiretroviral agents and the pyrimidine nucleoside analogue clevudine, and recent reports of myopathies caused by ingestion of red yeast rice and toxic species of mushrooms are also discussed.

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“…The in vitro/in vivo drug and metabolite transport/distribution and elimination behavior, especially in target organs, should be studied to add to the robustness of the PBPK model. In a recent study, involvement of the multidrug resistance-associated protein 1 for the efflux of rusovastatin in muscle, the target organ for rhadomyolosis, has been implied as a plausible cause of toxicity of the statin (Dorajoo et al, 2008); similar transporters of metabolites may need to be identified in toxicity evaluations. Through the refinement of modeling approaches by the incorporation of transporter and enzymes, a better solution may be on hand for metabolite toxicity testing and for the prediction of metabolite toxicity.…”

Section: Metabolite Kinetics In Intestinementioning

confidence: 99%

Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study

Sun

Pang²

2008

Drug Metab Dispos

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ABSTRACT:Metabolite in safety testing has been proposed for toxicity assessments. The question of how exposure of the synthetic metabolite compared with that of the formed metabolite was appraised kinetically by using physiologically based pharmacokinetic models, the (traditional) physiological model (TM), and segregated flow (SFM) models. The SFM differs from the TM and describes a partial (ϳ10% total) intestinal flow that perfuses the absorptive, metabolic, and secretory enterocyte layer to account for the higher extent of metabolism observed with oral versus systemic dosing of drugs. Theoretical solutions for the areas under the curve (AUC) of the formed metabolite after oral and intravenous administration of the precursor (AUC{mi,P}) and preformed, synthetic metabolite (AUC{pmi}) showed identical AUC iv {mi,P}, AUC po {mi,P}, and AUC po {pmi} for both the TM and SFM, whereas a larger AUC iv {pmi} existed for the SFM. The AUC{pmi} was influenced by metabolite parameters only: binding, absorptive (k a {mi}) and luminal degradation (k g {mi}) constants, intrinsic clearances for metabolism (CL int,met,I {mi}), apical efflux (CL int,sec,I {mi}), and basolateral transfer (CL d1 {mi} and CL d2 {mi}) for the metabolite. By contrast, the AUC{mi,P} was influenced additionally by precursor parameters: rate constants k a and k g , and CL int,met,I and CL int,sec,I , but not the basolateral transfer clearances. The drug parameters: CL int,met,I and k a increased whereas CL int,sec,I decreased AUC{mi,P}, and the effect of secretion was counterbalanced by reabsorption with high k a values. The simulated time courses for the metabolites and the AUC{pmi} and AUC{mi,P} resulting from intravenous and oral routes of administration of preformed metabolite and precursor differed, inferring that the kinetics of the preformed and formed metabolites are not identical.Metabolite-in-safety testing and the attainment of safe and efficacious drug use are key concerns in the drug development/surveillance paradigm. There has been a resurgence of interest in the testing of metabolites that are mediators of drug activity and toxicity due to the improvement in analytical methods for their detection, isolation, and characterization (Baillie et al., 2002). Metabolite testing is recommended, especially when metabolites are unique and identified only in humans, or when the metabolite exists at disproportionately higher levels in humans (Ͼ10%) than the animal species that was used for standard, nonclinical toxicology testing (Naito et al., 2007) (February, 2008 FDA Guidance for Industry, Safety Testing of Drug Metabolites. Pharmacology and Toxicology; http://www.fda.gov/cder/guidance/). It has been proposed that a metabolite is considered to be a major metabolite when the metabolite represents Ͼ10% (Davis-Bruno and Atrakchi, 2006) or 25% exposure (or area under the curve) of the precursor (Baillie et al., 2002). Others have suggested the estimate to be based on unbound concentration in the circulation or amounts in the excreta (Smith and Obach...

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Role of multi-drug resistance-associated protein-1 transporter in statin-induced myopathy

Cited by 14 publications

References 21 publications

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Update on Toxic Myopathies

Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study

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