Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?

PURPOSE: Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. METHODS: Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. RESULTS: Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. CONCLUSION: Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States.

PURPOSE: Systemic exposure to rosuvastatin in Asian subjects living in Japan or Singapore is approximately twice that observed in Caucasian subjects in Western countries or in Singapore. This study was conducted to determine whether pharmacokinetic differences exist among the most populous Asian subgroups and Caucasian subjects in the USA. METHOD: Rosuvastatin pharmacokinetics was studied in Chinese, Filipino, Asian-Indian, Korean, Vietnamese, Japanese and Caucasian subjects residing in California. Plasma concentrations of rosuvastatin and metabolites after a single 20-mg dose were determined by mass spectrometric detection. The influence of polymorphisms in SLCO1B1 (T521>C [Val174Ala] and A388>G [Asn130Asp]) and in ABCG2 (C421>A [Gln141Lys]) on exposure to rosuvastatin was also assessed. RESULTS: The average rosuvastatin area under the curve from time zero to time of last quantifiable concentration was between 64 and 84 % higher, and maximum drug concentration was between 70 and 98 % higher in East Asian subgroups compared with Caucasians. Data for Asian-Indians was intermediate to these two ethnic groups at 26 and 29 %, respectively. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin lactone were observed. Rosuvastatin exposure was higher in subjects carrying the SLCO1B1 521C allele compared with that in non-carriers of this allele. Similarly, exposure was higher in subjects carrying the ABCG2 421A allele compared with that in non-carriers. CONCLUSION: Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.

Epigenetic silencing of the endothelin-B receptor gene in non-small cell lung cancer.

Endothelin-1 is overexpressed in several tumor types. Activation of the endothelin-A (ETA) receptor may promote cell growth, angiogenesis and invasion, and inhibits the apoptotic process, while activation of the endothelin-B (ETB) receptor may induce cell death by apoptosis and inhibit tumor progression. Hypermethylation and subsequent silencing of the ETB receptor gene promoter has been reported in some cancer types. As the endothelin pathway is subject to research for pharmacological cancer treatment, we investigated the extent of epigenetic deregulation of the ETB receptor gene in non-small cell lung cancer (NSCLC). We scanned 64 NSCLC paired tumor/normal surgical specimens for the ETB receptor promoter for methylation by developing four pyrosequencing assays that covered 24 CpGs. The ETB receptor promoter was significantly hypermethylated in 31 (48%) of tumor samples, presenting considerably higher methylation in 22/24 CpG sites compared with the normal counterpart tissues. ETB receptor mRNA levels were reduced in all lung tumors compared with normal adjacent lung tissue, indicating the potentially important involvement of this gene in lung cancer development. Furthermore, tumor samples with ETB receptor gene methylation tended to have lower receptor mRNA levels compared with unmethylated tumor specimens, suggesting a primary epigenetic role in ETB receptor silencing. Our results point to a significant involvement of ETB receptor epigenetic deregulation in the pathogenesis of lung cancer making the gene a promising candidate biomarker for response to regimens modulating the endothelin axis.

Evaluation of cerebrospinal fluid proteins as potential biomarkers for early stage Parkinson's disease diagnosis.

Cerebrospinal fluid (CSF) has often been used as the source of choice for biomarker discovery with the goal to support the diagnosis of neurodegenerative diseases. For this study, we selected 15 CSF protein markers which were identified in previously published clinical investigations and proposed as potential biomarkers for PD diagnosis. We aimed at investigating and confirming their suitability for early stage diagnosis of the disease. The current study was performed in a two-fold confirmatory approach. Firstly, the CSF protein markers were analysed in confirmatory cohort I comprising 80 controls and 80 early clinical PD patients. Through univariate analysis we found significant changes of six potential biomarkers (α-syn, DJ-1, Aß42, S100ß, p-Tau and t-Tau). In order to increase robustness of the observations for potential patient differentiation, we developed-based on a machine learning approach-an algorithm which enabled identifying a panel of markers which would improve clinical diagnosis. Based on that model, a panel comprised of α-syn, S100ß and UCHL1 were suggested as promising candidates. Secondly, we aimed at replicating our observations in an independent cohort (confirmatory cohort II) comprising 30 controls and 30 PD patients. The univariate analysis demonstrated Aß42 as the only reproducible potential biomarker. Taking into account both technical and clinical aspects, these observations suggest that the large majority of the investigated CSF proteins currently proposed as potential biomarkers lack robustness and reproducibility in supporting diagnosis in the early clinical stages of PD.

Further evidence of association of OPRD1 & HTR1D polymorphisms with susceptibility to anorexia nervosa.

BACKGROUND: A recent study reported strong evidence for the involvement of a region on human chromosome 1 and genetic susceptibility to anorexia nervosa (AN). A more detailed analysis of this region has suggested 2 genes that may account for this susceptibility. These data suggest that polymorphisms in both the serotonin 1D (HTR1D) and opioid delta 1 (OPRD1) receptor genes show a significant association with restricting AN (RAN). METHODS: In the current study, we have conducted an independent association study on 226 females meeting DSM-IV criteria for AN and 678 matched volunteers. RESULTS: We genotyped 4 SNPs in HTR1D and 6 SNPs in OPRD1. 3 SNPs were found to be associated with both RAN and binge-purge AN (BPAN) within the gene for OPRD1. We also found evidence of association between 2 polymorphisms within HTR1D and RAN. CONCLUSIONS: These data support the hypothesis that polymorphisms within this region form a component of the genetic basis to susceptibility to RAN. However, further work is required to understand the processes that may be mediated by these genes.

ADRB2 polymorphisms and budesonide/formoterol responses in COPD.

BACKGROUND: Effects of ß(2)-adrenergic receptor gene (ADRB2) polymorphism on therapeutic responses to long-acting ß(2)-adrenergic agonists have not been evaluated in long-term COPD trials. We aimed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD. METHODS: Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I (NCT00206167) or the 6-month trial II (NCT00206154) were randomly assigned to bid budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9 µg or 160/9 µg, budesonide pMDI 320 µg + formoterol dry powder inhaler 9 µg (trial II), budesonide pMDI 320 µg (trial II), formoterol dry powder inhaler 9 µg, or placebo. The effect of Gly16Arg on predose FEV(1) and 1-h postdose FEV(1), exacerbations, diary variables, and adverse events were analyzed. RESULTS: No significant interaction between genotype and treatment response was observed for predose (P ≥ .197) or postdose FEV(1) (P ≥ .125) in either pharmacogenetic study (n = 2,866). The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups (both studies). Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment. CONCLUSION: Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD.

Evidence of complex involvement of serotonergic genes with restrictive and binge purge subtypes of anorexia nervosa.

OBJECTIVES: There is mixed evidence of association of serotoninergic genes with anorexia nervosa (AN), but substantial evidence for the involvement of serotonergic mechanisms in appetite control. This study was designed to investigate possible associations between the two subtypes of AN (Restricting-RAN, and Binge-purging-BPAN) and polymorphisms within five genes encoding for proteins involved in the serotoninergic system. METHODS: In order to carry out this investigation we have conducted a case-control association study on 226 females meeting the criteria for AN, and 678 matched healthy females. RESULTS: Our data show a significant association between polymorphisms with the gene encoding HTR2A with both AN subtypes, an association between polymorphisms within the genes encoding HTR1D and HTR1B with RAN, and an association between polymorphisms within the gene encoding HTR2C with BPAN. No associations were found for any polymorphisms of the serotonin transporter gene. This outcome indicates a substantial and complex inter-relationship between serotoninergic genes and AN. CONCLUSIONS: Given these data we hypothesis that the expression or control of expression of several genes of the serotoninergic system, and interactions between these genes, could exert considerable influence over the specific symptomatology of the subtypes of AN.