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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Inhibitors of CYP2C9 can cause serious drug–drug interactions when added to a therapeutic regimen with low therapeutic index drugs like S-warfarin, tolbutamide, or phenytoin. Life-threatening bleeding episodes, hypoglycemia, and neurotoxicity are the results of eliminating the enzymatic activity of CYP2C9 in these patients. One of the highly selective CYP2C9 competitive inhibitor is sulfaphenazole, which has poor affinity to other CYP2C subfamily (Ha-Duong et al. 2001a). Tienilic acid is a mechanism-based inactivator of CYP2C9 (Beaune et al. 1987; Dansette et al. 1992).
The Effects of Experimental Diabetes on the Cytochrome P450 System and Other Metabolic Pathways
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Costas Ioannides, Peter R. Flatt, Christopher R. Barnett
CYP2C — This is a large subfamily that plays an important role in the metabolism of many drugs such as tolbutamide, warfarin, hydantoins, and diclofenac.14 It also catalyzes the activation of the diuretic drug tienilic acid to form a protein-interacting intermediate which is responsible for its immunotoxicity (see above). An important aspect of this family is its genetic polymorphism, resulting in slow and fast metabolizers of drugs such as tolbutamide and mephenytoin.
Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism
Published in Xenobiotica, 2022
Rebecca Law, David Lewis, Daniel Hain, Rachel Daut, Melissa P. DelBello, Jean A. Frazier, Jeffrey H. Newcorn, Erika Nurmi, Elizabeth S. Cogan, Susanne Wagner, Holly Johnson, Jerry Lanchbury
ATX showed the highest amount of parent loss (86.9%; Table 2), which was inhibited 100% by paroxetine, a potent CYP2D6 inhibitor (Table 3). The formation of 4-OH-ATX, 4-OH-ATX-O-glucuronide, and N-desmethyl-OH-ATX was also inhibited by 86.4%, 93%, and 100%, respectively, by paroxetine (Table 3, Supplemental Table 3). Phencyclidine, a strong CYP2B6 and moderate CYP2D6 inhibitor (Kazmi, Yerino, Ogilvie, et al. 2014; Yang et al. 2016), also decreased the parent loss of ATX and subsequent formation of 4-OH-ATX, 4-OH-ATX-O-glucuronide, and N-desmethyl-OH-ATX by 45%, 29.5%, 30.6%, and 45.4%, respectively (Table 3, Supplemental Table 3). Ketoconazole, a CYP3A4/5 inhibitor, was the only other inhibitor to show a minor impact on ATX metabolism; it inhibited the formation of N-desmethyl-ATX by 24.8%. Additionally, 2-hydroxy-ATX did not have an available reference standard and was therefore detected with four different retention times across experiments. Different inhibition profiles were observed for each retention time, with a moderate effect of ketoconazole and esomeprazole, and a stronger effect of tienilic acid most often observed (Supplemental Table 3).
In vitro assessment of the inhibitory effect of goreisan extract and its ingredients on the P-glycoprotein drug transporter and cytochrome P-450 metabolic enzymes
Published in Xenobiotica, 2022
Mikina Takiyama, Takashi Matsumoto, Noriko Kaifuchi, Yasuharu Mizuhara, Eiji Warabi, Katsuya Ohbuchi, Kazushige Mizoguchi
Inhibitory effect of alisol A, tumulosic acid, and (E)-cinnamic acid on CYP450 enzyme activity. The remaining activity was calculated from the mean activity of duplicate samples. Positive controls to evaluate direct inhibition included CYP1A2, α-naphthoflavone (0.05 μmol/L); CYP2B6, ticlopidine (3 μmol/L); CYP2C8, montelukast (1 μmol/L); CYP2C9, sulfaphenazole (5 μmol/L); CYP2C19, tranylcypromine (50 μmol/L); CYP2D6, quinidine (5 μmol/L); and CYP3A, ketoconazole (0.2 μmol/L). Positive control to evaluation for time-dependent inhibition: CYP1A2, furafylline (1 μmol/L); CYP2B6, ticlopidine (0.1 μmol/L); CYP2C8, gemfibrozil 1-O-β-glucuronide (10 μmol/L); CYP2C9, tienilic acid (0.3 μmol/L); CYP2C19, S-fluoxetine (10 μmol/L); CYP2D6, paroxetine (0.3 μmol/L); and CYP3A, verapamil (3 μmol/L).
Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data
Published in Drug Metabolism Reviews, 2021
Jaydeep Yadav, Mehdi El Hassani, Jasleen Sodhi, Volker M. Lauschke, Jessica H. Hartman, Laura E. Russell
Miura et al. recently investigated the respective roles of cytochromes P450 2C9 and 3 A in the oxidation of (S)-warfarin and diclofenac in a chimeric mice model transplanted with human hepatocytes (Miura et al. 2020). The targeted expression of the herpes simplex virus type 1 thymidine kinase in the liver of severely immunodeficient mice enabled the mice livers to be replaced with mature and functional human liver tissue (Hasegawa et al. 2011). The humanized-liver mice were orally pretreated with 15 mg/kg tienilic acid to metabolically inactivate CYP2C9 and then treated with a single dose of 0.50 mg/kg (S)-warfarin or 10 mg/kg diclofenac. (S)-warfarin 7′-hydroxylation was significantly reduced in the CYP2C9-inactivated mice as demonstrated by a decrease in 7-hydroxywarfarin Cmax and AUCinfinity of 22% and 16%, respectively. This study suggests that humanized-liver mice pretreated with tienilic acid could serve as a potential in vivo model for metabolically inactivated CYP2C9. Such models could be useful to determine fm (fraction metabolized by each CYP isoform) of victim drugs in vivo (Miura et al. 2020).