Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care

Background-A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results-In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T\u3eC (P\u3c0.001) and ABCG2 c.421C\u3eA (P\u3c0.01) were important to rosuvastatin concentration (adjusted R2=0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A\u3eG (P\u3c0.01) and c.521T\u3eC (P\u3c0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient\u27s risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions-Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy. © 2013 American Heart Association, Inc

Resveratrol (trans-resveratrol, 3,5,4-trihydroxy-transstilbene) glucuronidation exhibits atypical enzyme kinetics in various protein sources. Drug Metab Dispos 36:322–330

ABSTRACT: The dietary polyphenol trans-resveratrol (3,5,4-trihydroxy-transstilbene) is glucuronidated at the 3 and 4 positions to yield two major glucuronide conjugates, resveratrol-3-O-glucuronide (R3G) and resveratrol-4-O-glucuronide (R4G). The major enzymes catalyzing this conjugation reaction are members of the UDPglucuronosyl transferase (UGT) 1A family and include UGT1A1 and UGT1A9, with minor contributions by UGT1A10. The kinetics of resveratrol glucuronidation in these three UGT1A isoforms as well as in human liver and intestinal microsomes were characterized across a wide concentration range. Atypical kinetics were observed for resveratrol glucuronidation in all the protein sources studied. The V max estimate per total protein for both glucuronides was higher in human intestinal microsomes compared with human liver microsomes (12.2 ؎ 0.34 versus 7.4 ؎ 0.25 nmol/min/mg for R3G and 8.9 ؎ 0.14 versus 0.45 ؎ 0.01 nmol/min/mg for R4G). The kinetic profile for formation of R3G in both human liver and intestinal microsomes fits a substrate inhibition model, whereas that for R4G exhibited a biphasic kinetic profile in human liver microsomes and substrate inhibition in human intestinal microsomes. In recombinant human UGT supersomes, for both glucuronides, UGT1A9 exhibited higher activity than UGT1A1, whereas the lowest activity was observed with UGT1A10. The kinetic profile for R3G exhibited substrate inhibition for all three isoforms, whereas that for R4G differed, exhibiting substrate inhibition for UGT1A1 and UGT1A10 and Hill kinetics for UGT1A9. These results suggest that in vitro kinetics of resveratrol glucuronidation at high concentrations cannot be ignored in predicting in vivo clearance upon highdose consumption of resveratrol

Gender-gap in randomized clinical trials reporting mortality in the perioperative setting and critical care: 20 years behind the scenes

Background: Women researchers might experience obstacles in academic environments and might be underrepresented in the authorship of articles published in peer-reviewed journals. Material and Methods: This is a cross-sectional analysis of female-led RCTs describing all interventions reducing mortality in critically ill and perioperative patients from 1981 to December 31, 2020. We searched PubMed/MEDLINE and EMBASE with the keywords RCTs and mortality. The gender of the first author was extracted and descriptive analysis was performed including the year of publication, impact factor, country of the first author, and methodological aspects. Results: We analyzed 340 RCTs, of which 42 (12%) were led by female researchers. The presence of women increased from 8% (14/172) until 2010 up to 17% (28/168) in 2010 and beyond. The United States, the United Kingdom, and Brazil were the main countries of origin of female researchers. Women authors conducted mainly single-center and single-nation studies as compared to male authors. The median impact factor of the target journal was 6 (3-27) in women vs. 7 (3-28) in men, with a p-value of 0.67; Critical Care Medicine, JAMA, and The New England Journal of Medicine were the most frequent target journals for both women and men. Conclusion: In the last 40 years, only one out of eight RCTs had a woman as the first author but the presence of women increased up to 17% by 2010 and beyond. The impact factor of publication target journals was high and not different between genders

Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentrations in Routine Clinical Care

BACKGROUND: A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. METHODS AND RESULTS: In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for gender, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (p < 0.001) and ABCG2 c.421C>A (p < 0.01) were important to rosuvastatin concentration (adjusted R(2) = 0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (p < 0.01) and c.521T>C (p < 0.05), and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R(2) = 0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90(th) percentile. CONCLUSIONS: Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine if this approach reduces incidence of statin-myopathy

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy

The human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy

The human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes