Utility of metaSite in improving metabolic stability of the neutral indomethacin amide derivative and selective cyclooxygenase-2 inhibitor 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-A/-phenethyl-acetamide

Drug Metabolism and Disposition

Volumn 37, Issue 5, 2009, Pages 999-1008

  Boyer, David ^a   Bauman, Jonathan N ^a   Walker, Daniel P ^a   Kapinos, Brendon ^a   Karki, Kapil ^a   Kalgutkar, Amit S ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [1 (4 CHLOROBENZOYL) 5 METHOXY 2 METHYL 1H INDOL 3 YL] N (4 FLUOROPHENYL)ACETAMIDE; 2 [1 (4 CHLOROBENZOYL) 5 METHOXY 2 METHYL 1H INDOL 3 YL] N (6 FLUOROPYRIDIN 3 YL)ACETAMIDE; 2 [1 (4 CHLOROBENZOYL) 5 METHOXY 2 METHYL 1H INDOL 3 YL] N PHENETHYLACETAMIDE; 2 [2 (1 (4 CHLOROBENZOYL) 5 METHOXY 2 METHYL 1H INDOL 3 YL)ACETAMIDO]ACETIC ACID; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; DRUG METABOLITE; INDOMETACIN; INDOMETACIN DERIVATIVE; KETOCONAZOLE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; COMPUTER MODEL; COMPUTER PROGRAM; CONTROLLED STUDY; DEMETHYLATION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG METABOLISM; DRUG OXIDATION; DRUG STABILITY; DRUG STRUCTURE; HUMAN; LIVER MICROSOME METABOLISM; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; RAT; TIME TO MAXIMUM PLASMA CONCENTRATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; AREA UNDER CURVE; BIOTRANSFORMATION; COMPUTER SIMULATION; CYCLOOXYGENASE 2 INHIBITORS; CYTOCHROME P-450 ENZYME SYSTEM; INDOMETHACIN; MALE; MASS SPECTROMETRY; MICROSOMES, LIVER; RATS; RATS, SPRAGUE-DAWLEY; SPECTROPHOTOMETRY, ULTRAVIOLET;

RATTUS;

EID: 66449136629     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.108.026112     Document Type: Article

References (20)

1. Ahlstrom MM, Ridderstrom M, Zamora I, and Luthman K (2007) CYP2C9 structure-metabolism relationships: optimizing the metabolic stability of COX-2 inhibitors. J Med Chem 50:4444-4452.
2. Apiwattanakul N, Sekine T, Chairoungdua A, Kanai Y, Nakajima N, Sophasan S, and Endou H (1999) Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes. Mol Pharmacol 55:847-854.
3. Bartolini W, Cali BM, Chen B, Chien YT, Currie MG, Milne GT, Pearson JP, Talley JJ, Yang JJ, Zimmerman C, et al. (2007) inventors; Microbia Inc., Bartolini W, Cali BM, Chen B, Chien YT, Currie MG, Milne GT, Pearson JP, Talley JJ, Yang JJ, Zimmerman C, et al., assignees. Useful indole compounds. World patent WO2007070892 (A2). 2007 June 21.
4. Caron G, Ermondi G, and Testa B (2007) Predicting the oxidative metabolism of statins: an application of the MetaSite® algorithm. Pharm Res 24:480-501.
5. Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C, Howe T, and Vianello R (2005) MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J Med Chem 48:6970-6979.
6. Dahlin DC, Miwa GT, Lu AY, and Nelson SD (1984) N-Acetyl-p- benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci U S A 81:1327-1331.
7. Dawidowicz AL, Kobielski M, and Pieniadz J (2008) Anomalous relationship between free drug fraction and its total concentration in drug-protein systems II. Binding of different ligands to plasma proteins. Eur J Pharm Sci 35:136-141.
8. Gao H, Yao L, Mathieu HW, Zhang Y, Maurer TS, Troutman MD, Scott DO, Ruggeri RB, and Lin J (2008) In silico modeling of nonspecific binding to human liver microsomes. Drug Metab Dispos 36:2130-2135.
9. Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP, and Marnett LJ (2000a) Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci USA 97:925-930.
10. Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, and Marnett LJ (2000b) Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxy- genase-2 inhibitors. J Med Chem 43:2860-2870.
11. Kouzuki H, Suzuki H, and Sugiyama Y (2000) Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res 17:432-438.
12. Lewis DF, Modi S, and Dickins M (2002) Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev 34:69 -82.
13. Nakajima M, Inoue T, Shimada N, Tokudome S, Yamamoto T, and Kuroiwa Y (1998) Cyto- chrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab Dispos 26:261-266.
14. Obach RS (1999) Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350-1359.
15. Obach RS, Kalgutkar AS, Soglia JR, and Zhao SX (2008) Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 21:1814-1822.
16. Paine SW, Parker AJ, Gardiner P, Webborn PJ, and Riley RJ (2008) Prediction of the pharma- cokinetics of atorvastatin, cerivastatin and indomethacin using kinetic models applied to isolated rat hepatocytes. Drug Metab Dispos 36:1365-1374.
17. Remmel RP, Crews BC, Kozak KR, Kalgutkar AS, Marnett LJ, and Algutkar AS (2004) Studies on the metabolism of the novel, selective cyclooxygenase-2 inhibitor indomethacin pheneth- ylamide in rat, mouse, and human liver microsomes: identification of active metabolites. Drug Metab Dispos 32:113-122.
18. Sabolovic N, Magdalou J, Netter P, and Abid A (2000) Nonsteroidal anti-inflammatory drugs and phenols glucuronidation in Caco-2 cells: identification of the UDP-glucuronosyltransferases UGT1A6, 1A3 and 2B7. Life Sci 67:185-196.
19. Zamora I, Afzelius L, and Cruciani G (2003) Predicting drug metabolism: a site of metabolism prediction tool applied to the cytochrome P450 2C9. J Med Chem 46:2313-2324.
20. Zhou D, Afzelius L, Grimm SW, Andersson TB, Zauhar RJ, and Zamora I (2006) Comparison of methods for the prediction of the metabolic sites for CYP3A4-mediated metabolic reactions. Drug Metab Dispos 34:976 -983.