8 14 dihydroxyefavirenz

Caffeine (1,3,7 TMX), 1‐methylxanthine (1 MX), 1‐methyluric acid (1 MU), 1,7‐dimethyluric acid (1,7 DMU), 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU), and 1,7‐dimethylxanthine (1,7 DMX) or paraxanthine and theobromine and theophylline were purchased from Sigma–Aldrich (St. Louis, MO). Efavirenz, 8‐hydroxyEfavirenz, 8,14‐dihydroxyEfavirenz, 7‐hydroxyEfavirenz, and β‐glucuronidase were purchased from Toronto Research Chemicals (North York, Ontario, Canada). All other chemicals and solvents were high‐performance liquid chromatography (HPLC) grade or the highest quality commercially available.

Caffeine-d9, ciprofloxacin, efavirenz-d4, 8-hydroxyefavirenz, 8,14-dihydroxyefavirenz, fluconazole, losartan, losartan carboxylic acid (E3174), losartan-d4, α-hydroxyMetoprolol, Metoprolol-d7, omeprazole, 5-hydroxyomeprazole, omeprazole-d3, paroxetine, and rifampicin were purchased from Toronto Research Chemicals (Toronto, Canada). 1’-HydroxyMidazolam and Midazolam-d6 were purchased from Lipomed (Lipomed AG, Arlesheim, Switzerland). Metoprolol, paraxanthine, and β-glucuronidase were obtained from Sigma-Aldrich (Sigma-Aldrich Chemie GmbH, Buchs, Switzerland). Midazolam (Hoffmann-La Roche, Basel, Switzerland) and efavirenz (Merck, NJ, USA) were kindly provided by the producers.
Formic acid, high-performance liquid chromatography (HPLC)-grade methanol, and water were purchased from Merck (Merck, Darmstadt, Germany). Stock solutions, calibration spiking solutions, and quality controls were prepared in dimethyl sulfoxide. Calibration standards were prepared by enriching caffeine-free blank human serum using the corresponding spiking solutions. Internal standard solutions containing the deuterated compounds were prepared in methanol.