Identification of enzymes responsible for the N-oxidation of darexaban glucuronide, the pharmacologically active metabolite of darexaban, and the glucuronidation of darexaban N-oxides in human liver microsomes

Biological and Pharmaceutical Bulletin

Volumn 35, Issue 3, 2012, Pages 413-421

  Shiraga, Toshifumi ^a   Yajima, Kanako ^b   Teragaki, Takuya ^b   Suzuki, Katsuhiro ^a   Hashimoto, Tadashi ^a   Iwatsubo, Takafumi ^a   Miyashita, Aiji ^a   Usui, Takashi ^a  

^a ASTELLAS PHARMA INC   (Japan)

^b SHIN NIPPON BIOMEDICAL LABORATORIES LTD   (Japan)

Author keywords

Darexaban; Flavin containing monooxygenase 3; Glucuronidation; N oxidation; Pharmacologically active metabolite; Uridine 5 diphosphate glucuronosyltransferase 1A9

Indexed keywords

CYTOCHROME P450 1A2; CYTOCHROME P450 2A6; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DAREXABAN; DAREXABAN GLUCURONIDE; DIMETHYLANILINE MONOOXYGENASE; DRUG METABOLITE; GLUCURONOSYLTRANSFERASE 1A10; GLUCURONOSYLTRANSFERASE 1A7; GLUCURONOSYLTRANSFERASE 1A8; GLUCURONOSYLTRANSFERASE 1A9; MESSENGER RNA; OXIDE; RECOMBINANT ENZYME; THIAMAZOLE; UNCLASSIFIED DRUG;

ARTICLE; CATALYSIS; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME KINETICS; ENZYME METABOLISM; GLUCURONIDATION; HUMAN; HUMAN CELL; IN VITRO STUDY; LIQUID CHROMATOGRAPHY; LIVER MICROSOME; MASS SPECTROMETRY; OXIDATION;

AZEPINES; BENZAMIDES; CYTOCHROME P-450 ENZYME SYSTEM; FACTOR XA; GLUCURONIDES; GLUCURONOSYLTRANSFERASE; HUMANS; MICROSOMES, LIVER; OXIDATION-REDUCTION; OXYGENASES; PROTEIN ISOFORMS; RECOMBINANT PROTEINS;

EID: 84863294154     PISSN: 09186158     EISSN: 13475215     Source Type: Journal    
DOI: 10.1248/bpb.35.413     Document Type: Article

References (26)

1. Eriksson BI, Turpie AG, Lassen MR, Prins MH, Agnelli G, Kälebo P, Wetherill G, Wilpshaar JW, Meems L; ONYX-2 STUDY GROUP. Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2). J. Thromb. Haemost., 8, 714-721 (2010).
2. Hirayama F, Koshio H, Ishihara T, Hachiya S, Sugasawa K, Koga Y, Seki N, Shiraki R, Shigenaga T, Iwatsuki Y, Moritani Y, Mori K, Kadokura T, Kawasaki T, Matsumoto Y, Sakamoto S, Tsukamoto S. Discovery of N-[2-hydroxy-6-(4- methoxybenzamido)phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa Inhibitor. J. Med. Chem., 54, 8051-8065 (2011).
3. Iwatsuki Y, Sato T, Moritani Y, Shigenaga T, Suzuki M, Kawasaki T, Funatsu T, Kaku S. Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor. Eur. J. Pharmacol., 673, 49-55 (2011).
4. Groenendaal - van de Meent D, Heeringa M, Kadokura T, Verheggen F, Strabach G, Heinzerling H. YM150, an oral direct inhibitor of factor Xa, demonstrated a predictable and dose-proportional pharmacokinetic/pharmacodynamic profile after single and multiple dosing: results from three studies. Blood, 116, 3323 (2010), Abstract.
5. Shiraga T, Yajima K, Suzuki K, Suzuki K, Hashimoto T, Iwatsubo T, Miyashita A, Usui T. Identification of UDPglucuronosyltransferases responsible for the glucuronidation of darexaban, an oral factor Xa inhibitor, in human liver and intestine. Drug Metab. Dispos., 40, 276-282 (2012).
6. Ortiz de Montellano PR, Mathews JM. Autocatalytic alkylation of the cytochrome P-450 prosthetic haem group by 1-aminobenzotriazole. Isolation of an NN-bridged benzyne-protoporphyrin IX adduct. Biochem. J., 195, 761-764 (1981).
7. Kedderis GL, Rickert DE. Loss of rat liver microsomal cytochrome P-450 during methimazole metabolism. Role of flavin-containing monooxygenase. Drug Metab. Dispos., 13, 58-61 (1985).
8. Newton DJ, Wang RW, Lu AYH. Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes. Drug Metab. Dispos., 23, 154-158 (1995).
9. Guo Z, Raeissi S, White RB, Stevens JC. Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab. Dispos., 25, 390-393 (1997).
10. Dierks EA, Stams KR, Lim HK, Cornelius G, Zhang H, Ball SE. A method for the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s using an in vitro cocktail of probe substrates and fast gradient liquid chromatography tandem mass spectrometry. Drug Metab. Dispos., 29, 23-29 (2001).
11. Zhang W, Kilicarslan T, Tyndale RF, Sellers EM. Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab. Dispos., 29, 897-902 (2001).
12. Suzuki H, Kneller MB, Haining RL, Trager WF, Rettie AE. (+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19. Drug Metab. Dispos., 30, 235-239 (2002).
13. Linder CD, Renaud NA, Hutzler JM. Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab. Dispos., 37, 10-13 (2009).
14. Fisher MB, Campanale K, Ackermann BL, VandenBranden M, Wrighton SA. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab. Dispos., 28, 560-566 (2000).
15. Watanabe Y, Nakajima M, Yokoi T. Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab. Dispos., 30, 1462-1469 (2002).
16. Yamanaka H, Nakajima M, Katoh M, Yokoi T. Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes. Drug Metab. Dispos., 35, 1642-1648 (2007).
17. Itäaho K, Mackenzie PI, Ikushiro S, Miners JO, Finel M. The configuration of the 17-hydroxy group variably influences the glucuronidation of β-estradiol and epiestradiol by human UDP-glucuronosyltransferases. Drug Metab. Dispos., 36, 2307-2315 (2008).
18. Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro - in vivo extrapolation of drug clearance and drug - drug interaction potential. Drug Metab. Rev., 42, 196-208 (2010).
19. Zhang J, Cashman JR. Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab. Dispos., 34, 19-26 (2006).
20. Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol., 40, 581-616 (2000).
21. Gregory PA, Lewinsky RH, Gardner-Stephen DA, Mackenzie PI. Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. Toxicol. Appl. Pharmacol., 199, 354-363 (2004).
22. Ohno S, Nakajin S. Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab. Dispos., 37, 32-40 (2009).
23. Izukawa T, Nakajima M, Fujiwara R, Yamanaka H, Fukami T, Takamiya M, Aoki Y, Ikushiro S, Sakaki T, Yokoi T. Quantitative analysis of UDP- glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers. Drug Metab. Dispos., 37, 1759-1768 (2009).
24. Rowland A, Gaganis P, Elliot DJ, Mackenzie PI, Knights KM, Miners JO. Binding of inhibitory fatty acids is responsible for the enhancement of UDP-glucuronosyltransferase 2B7 activity by albumin: implications for in vitro - in vivo extrapolation. J. Pharmacol. Exp. Ther., 321, 137-147 (2007).
25. Rowland A, Knights KM, Mackenzie PI, Miners JO. The "albumin effect" and drug glucuronidation: bovine serum albumin and fatty acid-free human serum albumin enhance the glucuronidation of UDP-glucuronosyltransferase (UGT) 1A9 substrates but not UGT1A1 and UGT1A6 activities. Drug Metab. Dispos., 36, 1056-1062 (2008).
26. Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab. Dispos., 37, 82-89 (2009).