aCardiovascular Research Institute bDepartment of Dermatology cInstitute for Human Genetics dDepartment of Bioengineering and Therapeutic Sciences eThe Liver Center, University of California, San Francisco, California fCardiovascular Health Research Unit Departments of gMedicine hEpidemiology iHealth Services jMedicinal Chemistry, University of Washington kGroup Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
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.
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.
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.
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.
"Gastrointestinal and neurological symptoms, psychiatric symptoms, sleep problems, glucose elevations and a range of other symptoms reported on statins also arise in mitochondrial dysfunction            . Also asymptomatic elevation of hepatic transaminases and extremely rare cases of hepatitis were also seen . N o v a P u b l i s h e r s I n c . "
[Show abstract][Hide abstract] 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
"Statins therapeutic actions and most importantly, adverse effects which include myopathy and rhabdomyolysis have shown great inter-individual and ethnic variations (17, 18). These inter-individual and ethnic variations in the therapeutic response and severity of adverse effects are largely attributed to the genetic variations therefore predisposing to altered drug disposition (16, 19, 20). Identification and characterization of underlying genetic variations will help us towards better dosing regimens and safer drug designs for personalized therapy. "
[Show abstract][Hide abstract] ABSTRACT: Objective(s):
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.
Materials and Methods:
Frequencies of alleles, genotype, and haplotypes of two functionally significant Single nucleotide polymorphism in 180 healthy Pakistani subjects and distributions in six ethnic groups by using a single step T. ARMS genotyping assay.
The allelic frequency for 388A>G SNP was 50% in total Pakistani population with Single nucleotide polymorphism distributions of 9.7%, 15.1%, 19.4%, 16.1%, 18.3%, and 21.5% in Punjabi, Sindhi, Balouchi, Pathan, Kashmiri and Hazara/Baltistan groups respectively; and for 521T>C SNP it was 23.9% in total Pakistani population with distributions of 11.1%, 8.9%, 15.6%, 11.1%, 31.1% and 22.2% in Punjabi, Sindhi, Balouchi, Pathan, Kashmiri, and Hazara/Baltistan groups. Both functionally significant SNPs occurred in four major haplotypes with a frequency of 35.5% for 388A/521T (*1A), 40.5% for 388G/521T (*1B), 14.4% for 388A/521C (*5), and 9.4% for 388G/521C (*15) with varying distributions among six ethnic groups.
The 388A>G and 521T>C genotypes and corresponding haplotypes are present at varying frequencies in various ethnic groups of Pakistani population. Pharmacokinetic and pharmacodynamic profiling is needed to assess and characterize the effects of these haplotypes in our population.
Iranian Journal of Basic Medical Science 06/2014; 17(6). · 1.23 Impact Factor
[Show abstract][Hide abstract] 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.
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