OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis.
ABSTRACT OBJECTIVE: Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. METHODS: This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. RESULTS: The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. CONCLUSION: Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1.
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ABSTRACT: Cardiovascular diseases (CVD) are common and very well-known diseases that affect a large number of people. One of the common leading causes of CVD is a high level of lipids which eventually leads to atherosclerosis and CVD. Various types of medications having different mechanisms of action were introduced to control CVD. Among the frequently used drugs is statins. Statins have a very intense effect on lowering lipids, yet they are associated with a variety of side effects. Moreover, statins have low bioavailability, similarly to other lipid lowering medications. Therefore, several attempts were made to enhance their bioavailability. This chapter discusses a number of drugs used to lower lipid levels in the blood, their adverse effects and methods to improve their bioavailability.Commonly Used Drugs - Uses, Side Effects, Bioavailability & Approaches to Improve it, 1 edited by Rafik Karaman, 01/2015: chapter 4: pages 131-172; Nova Science Publishers., ISBN: 978-1-63463-828-9
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ABSTRACT: Bosentan (Tracleer®) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with ALT, AST and DILI. After adjusting for BMI, CYP2C9*2 was the only polymorphism associated with ALT, AST and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; OR 95% CI = 2.29 - ∞, P = 0.003, respectively). Bosentan metabolism in vitro by CYP2C9*2 was significantly reduced compared to CYP2C9*1 and was comparable to CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 17 July 2013 doi:10.1038/clpt.2013.143.Clinical Pharmacology & Therapeutics 07/2013; 94(6). DOI:10.1038/clpt.2013.143 · 7.39 Impact Factor
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ABSTRACT: Organic anion transporter polypeptide 1B1 (OATP1B1) encoded by solute carrier organic transporter 1B1 (SLCO1B1) gene; a transporter involved in the uptake of drugs and endogenous compounds is present in hepatocyte sinusoidal membrane. Aim of this study was to investigate the frequencies of functionally significant SNPs (388A>G and 521T>C) and their haplotypes in 6 ethnic groups of Pakistani population through the development of rapid and efficient Tetra amplification refractory mutation system (T. ARMS) genotyping assay.Iranian Journal of Basic Medical Science 06/2014; 17(6). · 0.60 Impact Factor