Midazolam

S. flavescens root extract was purchased from the Korea Plant Extract Bank (Chungbuk, Korea). The extract was prepared by extraction with a 70% ethanol solution. Glucose 6-phosphate, β-NADP+, glucose-6-phosphate dehydrogenase, phenacetin, coumarin, bupropion, diclofenac, S-mephenytoin, dextromethorphan, and chlorpropamide were purchased from Sigma Aldrich (St. Louis, MO, USA); rosiglitazone and midazolam from Toronto Research Chemicals (Toronto, ON, Canada); and kushenols A, C, I, and M, leachianone A, and sophoraflavone G from Core Sciences (Seoul, Korea). Pooled human liver microsomes, and baculovirus-insect cell expressed 2B6 and 3A4 were purchased from BD Gentest (Woburn, MA, USA). All other reagents were of the highest grade commercially available.

The following chemicals were obtained from Sigma-Aldrich (St. Louis, MO, USA): amodiaquine, bupropion, chlorzoxazone, dextromethorphan, 7-ethoxyresorufin, glucose-6-phosphate (G6P), G6P dehydrogenase (G6PDH), β-nicotinamide adenine dinucleotide phosphate (NADP⁺), omeprazole, phenacetin, and trimipramine. Coumarin, midazolam, and tolbutamide were obtained from Toronto Research Chemicals (Toronto, ON, Canada). We purchased resorufin from Tokyo Chemical Industry (Tokyo, Japan). Pooled human liver microsomes (pHLMs, XTreme 200) were obtained from XenoTech (Kansas City, KS, USA), and human recombinant CYP1A1 (rCYP1A1) and CYP1A2 (rCYP1A2) isoforms were obtained from SPMED (Busan, Republic of Korea). Chrysophanol (95.0% purity), emodin (94.3% purity), obtusifolin (95.4% purity), physcion (95.0% purity), and rubrofusarin (90.0% purity) (Figure 1) were kindly provided by the Korea Institute of Science and Technology (Gangneung, Republic of Korea).

TaKaRa MiniBEST Whole Blood Genomic DNA Extraction Kit, PrimeSTAR HS DNA polymerase, restriction enzymes, and T4 DNA ligase were purchased from Takara Bio Inc. (Kusatsu, Japan). Spodoptera frugiperda (Sf) 21 cells, fetal bovine serum, Sf-900™ III SFM insect culture medium, Cellfectin II Reagent, and the Bac-to-Bac™ Baculovirus Expression System were purchased from Invitrogen (Carlsbad, CA, United States). Tolbutamide, 4-hydroxy Tolbutamide, losartan, losartan carboxylic acid, warfarin, 7-hydroxy warfarin, diazepam and midazolam (internal standard [IS]) were purchased from Toronto Research Chemicals (Toronto, Canada). Rabbit polyclonal anti-CYP2C9 antibody and mouse monoclonal anti-OR antibody were obtained from Abcam (Cambridge, United Kingdom) and Santa Cruz Biotechnology (Santa Cruz, CA, United States), respectively. A SuperSignal West Pico Trial Kit was obtained from Thermo Scientific (Rockford, IL, United States). A regeneration system for the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) was obtained from Promega (Madison, WI, United States). High-performance liquid chromatography-grade organic solvents and liquid chromatography–mass spectrometry-grade acetonitrile were purchased from Merck (Darmstadt, Germany). All other chemicals and reagents used were of the highest purity available.

Trans-resveratrol (tRVT, purity ≥ 99%), cis-resveratrol (cRVT, purity ≥ 98%), dehydronifedipine, diclofenac, 6-hydroxychlorzoxazone, 4-hydroxydiclofenac, 4-hydroxymephenytoin, S-mephenytoin, midazolam, mycophenolic acid (MPA), nifedipine, CDCA-24-acyl-β-glucuronide, 7-ethyl-10-hydroxy camptothecin (SN-38) glucuronide, MPA-β-d-glucuronide, and N-acetylserotonine (N-ASER)-β-d-glucuronide were obtained from Toronto Research Chemicals (Toronto, ON, Canada). Acetaminophen, amodiaquine, bupropion, chenodeoxycholic acid (CDCA), chlorzoxazone, dextromethorphan, dextrorphan, 6-hydroxybupropion, 7-hydroxycoumarin, N-ASER, N-desethylamodiaquine, naloxone, nifedipine, phenacetin, trifluoperazine (TFP), estrone-β-d-glucuronide, naloxone-β-d-glucuronide, and TFP-β-d-glucuronide were obtained from Sigma-Aldrich (St. Louis, MO, USA). SN-38 and 1′-hydroxymidazolam were provided by Santa Cruz Biotechnology (Dallas, TX, USA) and Cayman Chemicals (Ann Arbor, MI, USA), respectively. Pooled HLMs (XTreme 200) were purchased by XenoTech (Lenexa, KS, USA). rP450 (rCYP3A4, rCYP2E1, rCYP2C19, and rCYP1A2) were obtained from SPMED (Busan, Korea).

TFDS Capsules (0.2 g/capsule), containing 133 mg of TFDS extract with 8.5 mg schaftoside per capsule, and the TFDS APIs were supplied by Humanwell Healthcare (Group) Co., Ltd. The reference standards of schaftoside and sulfamethoxazole were provided by Chinese National Institutes for Food and Drug Control (Beijing, China). Midazolam was supplied by Toronto Research Chemicals INC (Toronto, Canada). D-glucose-6-phosphate disodium salt hydrate, glucose-6-phosphate dehydrogenase, β-nicotinamide adenine dinucleotide phosphate sodium salt hydrate, and Midazolam were the products of Sigma-Aldrich Co. (St. Louis, United States). The liver microsomes of rat and human were purchased from Corning Gentest (Woburn, MA, United States). High-performance liquid chromatography (HPLC) grade acetonitrile, methanol and formic acid were supplied by Merck KGaA (Darmstadt, Germany). Ultrapure water was prepared by a Milli-Q water system (Millipore, United States) in our own lab. All the other reagents and solvents were commercially available.

Caffeine, omeprazole, and propranolol were purchased from Sigma-Aldrich (St. Louis, MO, USA). Dextromethorphan, dextrorphan, midazolam, 5′-hydroxyomeprazole, losartan, losartan carboxylic acid (EXP3174), paraxanthine, and pitavastatin were obtained from Toronto Research Chemicals Inc. (North York, ON, Canada). 1′-Hydroxymidazolam was purchased from Cayman Chemical (Ann Arbor, MI, USA). Solvents were LC-MS grade (Fisher Scientific Co., Pittsburgh, PA, USA) and the other chemicals were obtained from Sigma-Aldrich. Pooled human plasma was obtained from BioChemed Services (Winchester, VA, USA).