Heduled at the Geneva University Hospitals, more than a period of 16 months. Eligible individuals underwent an elective surgery for hip osteoarthritis and had been older than 18 years of age. Exclusion criteria incorporated pregnancy, breastfeeding, and allergy to any of the components in the Geneva cocktail (caffeine, flurbiprofen, omeprazole, bupropion, dextromethorphan, fexofenadine, and midazolam) at the same time as severe TLR8 Agonist drug cardiac failure, severe edema or ascites, serious chronic obstructive pulmonary illness or pulmonary embolism requiring oxygen, renal impairment (defined as serum creatinine concentrations 1.five upper limit regular), hepatic impairment (defined as transaminases, bilirubin, gamma glutamyl transferase two upper limit regular), HIV infection, active cancer, uncontrolled infection, or inflammatory arthritis. Moreover, comedications have been systematically screened and individuals taking CYP inhibitors or inducers had been excluded, applying the Lexi-Interact drug interaction checker as well as the Geneva table of CYP substrates, inhibitors, and inducers.16,17 Proton pump inhibitor use was permitted inside the postoperative setting, since it is actually a routine prescription soon after surgery in our hospital that could thus not be excluded. Esomeprazole was the onlyARTICLEproton pump inhibitor administered to the study subjects. The linear mixed model was hence adjusted for esomeprazole intake since it is a wellknown CYP2C19 inhibitor. The principal objective was to measure the variation in the activity of six key CYPs post hip surgery. Genotyping of CYP2D6, CYP2B6, CYP2C9, and CYP2C19 The method has previously been described in detail within the literature.18 Briefly, genomic DNA was extracted from EDTA complete blood samples making use of the QIAamp DNA blood mini kit (Qiagen, Hombrechtikon, Switzerland). Genotyping was performed employing TaqMan OpenArray genotyping assays (Life Technologies Corporation, Carlsbad, CA) on a QuantStudio 12K Flex Real-time PCR Program (Thermo Fisher Scientific, Rochester, NY). Single-nucleotide polymorphisms made use of to assess the CYP genotype are listed in Table S1. CYP2D6 gene duplication had been also assessed together with the TaqMan Copy Quantity Assay Hs00010001 with RNase P as references (Thermo Fisher Scientific). AlleleTyper Application (Thermo Fisher Scientific) was made use of to translate genetic pattern information and facts from genotyping (Single-nucleotide polymorphisms) and copy number assay to pharmacogenomic gene-level star () nomenclature. Translational tables (Thermo Fisher Scientific and PharmGKB) had been applied to identify genotype for every single CYP (star allele nomenclature). Phenotyping The metabolic ratio (MR) of 6 CYPs (1A2, 2B6, 2C9, 2C19, 2D6, and 3A) was measured just before surgery (D0), day 1 (D1) and day 3 (D3) after surgery and at discharge. Phenotype assessment was performed using the orally administrated probe substrates contained inside the Geneva cocktail (caffeine 50 mg, CYP1A2; bupropion 20 mg, CYP2B6; flurbiprofen ten mg, CYP2C9; omeprazole 10 mg, CYP2C19; dextromethorphan 10 mg, CYP2D6, and midazolam 1 mg, CYP3A). The absence of mutual drug-drug interactions within the Geneva cocktail was previously demonstrated and bupropion is applied at such a low dose that no impact on CYP2D6 activity is demonstrated.19 The cocktail was also previously validated employing dried blood spots as a sampling strategy. 20 Capillary blood samples have been collected 2 hours soon after drug administration within a fasting patient and dried blood spots were STAT3 Activator custom synthesis stored at 0 inside a sealable plastic bag till evaluation, as previously described.