Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19

Drug Metabolism and Disposition

Volumn 32, Issue 12, 2004, Pages 1462-1467

  Hirani, Vandana N ^a   Raucy, Judy L ^b   Lasker, Jerome M ^a  

^a HACKENSACK UNIVERSITY MEDICAL CENTER   (United States)

^b California Toxicol Res Institute   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 2C19; DIDANOSINE; INDINAVIR; MONOCLONAL ANTIBODY; NELFINAVIR; NEVIRAPINE; OMEPRAZOLE; PROTEINASE INHIBITOR; RIFAMPICIN; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; ZIDOVUDINE;

ANTIVIRAL ACTIVITY; ARTICLE; BIOAVAILABILITY; BIOTRANSFORMATION; CATALYSIS; DRUG INHIBITION; DRUG METABOLISM; ENZYME INDUCTION; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HUMAN TISSUE; HYDROXYLATION; LIVER METABOLISM; MICROSOME MEMBRANE; OPPORTUNISTIC INFECTION; PRIORITY JOURNAL;

ANTIBODIES, MONOCLONAL; ARYL HYDROCARBON HYDROXYLASES; BIOTRANSFORMATION; ENZYME INHIBITORS; HIV PROTEASE INHIBITORS; HUMANS; HYDROXYLATION; KINETICS; MICROSOMES, LIVER; MIXED FUNCTION OXYGENASES; NELFINAVIR; OMEPRAZOLE;

HUMAN IMMUNODEFICIENCY VIRUS;

EID: 9444245372     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: 10.1124/dmd.104.001743     Document Type: Article

References (35)

1. Baede-van Dijk PA, Hugen PW, Verweij-van Wissen CP, Koopmans PP, Burger DM, and Hekster YA (2001) Analysis of variation in plasma concentrations of nelfinavir and its active metabolite M8 in HIV-positive patients. AIDS 15:991-998.
2. Bergshoeff AS, Wolfs TF, Geelen SP, and Burger DM (2003) Ritonavir-enhanced pharmacokinetics of nelfinavir/M8 during rifampin use. Ann Pharmacother 37:521-525.
3. Chiba M, Hensleigh M, and Lin JH (1997a) Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Major role of CYP3A. Biochem Pharmacol 53:1187-1195.
4. Chiba M, Nshime JA, and Lin JH (1997b) In vitro metabolism of indinavir in the human fetal liver microsomes. Drug Metab Dispos 25:1219-1222.
5. Denissen JF, Grabowski BA, Johnson MK, Buko AM, Kempf DJ, Thomas SB, and Surber BW (1997) Metabolism and disposition of the HIV-1 protease inhibitor ritonavir (ABT-538) in rats, dogs and humans. Drug Metab Dispos 25:489-501.
6. Eagling VA, Back DJ, and Barry MG (1997) Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 44:190-194.
7. Feierman DE and Lasker JM (1996) Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos 24:932-939.
8. Finch CK, Chrisman CR, Baciewicz AM, and Self TH (2002) Rifampin and rifabutin drug interactions: an update. Arch Intern Med 162:985-992.
9. Fitzsimmons ME and Collins JM (1997) Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. Drug Metab Dispos 25:256-266.
10. Gerbal-Chaloin S, Pascussi J-M, Pichard-Garcia L, Daujat M, Waechter F, Fabre J-M, Carrere N, and Maurel P (2001) Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos 29:242-251.
11. Gillam EM, Guo Z, and Guengerich FP (1994) Expression of modified human cytochrome P450 2E1 in Escherichia coli, purification and spectral and catalytic properties. Arch Biochem Biophys 312:59-66.
12. Imaoka S, Imai Y, Shimada T, and Funae Y (1992) Role of phospholipids in reconstituted cytochrome P450 3A form and mechanism of their activation of catalytic activity. Biochemistry 31:6063-6069.
13. Jin R, Koop DR, Raucy JL, and Lasker JM (1998) Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4. Arch Biochem Biophys 359:89-98.
14. Karam WG, Goldstein JA, Lasker JM, and Ghanayem BI (1996) Human CYP2C19 is a major omeprazole 5-hydroxylase, as demonstrated with recombinant cytochrome P450 enzymes. Drug Metab Dispos 24:1081-1087.
15. Kerr B, Lee CA, Yuen G, Anderson R, Daniels R, and Grettenberger HM (1997) Overview of in vitro and in vivo drug interaction studies of nelfinavir mesylate, a new HIV-1 protease inhibitor, in 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22-26, Washington DC. Conference on Retroviruses and Opportunistic Infections, Alexandria, VA.
16. Koudriakova T, Iatsimirskaia E, Utkin I, Gangl E, Vouros P, Storozhuk E, Orza D, Marinina J, and Gerber N (1998) Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 26:552-561.
17. Krausz KW, Coldfarb I, Buters JTM, Yang TJ, Gonzalez FJ, and Gelboin HV (2001) Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9 and 2C19. Drug Metab Dispos 29:1410-1423.
18. Kumar GN, Rodrigues AD, Buko AM, and Denissen JF (1996) Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 277:423-431.
19. Lasker JM, Wester MR, Aramsombatdee E, and Raucy JL (1998) Characterization of CYP2C19 and CYP2C9 from human liver: respective roles in microsomal tolbutamide, S-mephenytoin and omeprazole hydroxylations. Arch Biochem Biophys 353:16-28.
20. Lillibridge JH, Lee CA, and Pithavala YK (1998a) The role of polymorphic CYP2C19 in the metabolism of nelfinavir mesylate, in XII Annual Meeting and Exposition of the American Association of Pharmaceutical Scientists; November 1998, San Francisco. Abstract 3035. American Association of Pharmaceutical Scientists, Arlington, VA.
21. Lillibridge JH, Lee CA, Pithavala YK, Sandoval TM, Wu EY, Zhang KE, Mazabel EL, Zhang M, and Kerr BM (1998b) The role of CYP2C19 in the formation of nelfinavir hydroxy-t-butylamide (M8): in vitro/in vivo correlation. Presented at the 5th International ISSX Meeting; 1998 Oct 25-29, Cairns, Australia. International Society for the Study of Xenobiotics, Potomac, MD.
22. Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shetty BV, and Lee CA (1998c) Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 26:609-616.
23. Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, d'Arminio Monforte A, Yust I, Bruun JN, Phillips AN, and Lundgren JD (1998) Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352:1725-1730.
24. Omura T and Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370-2378.
25. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, and Holmberg SD (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338: S53-S60.
26. Powell PK, Wolf I, and Lasker JM (1996) Identification of CYP4A11 as the major lauric acid omega-hydroxylase in human liver microsomes. Arch Biochem Biophys 335:219-226.
27. Raucy JL and Lasker JM (1991) Isolation of P450 enzymes from human liver. Methods Enzymol 206:577-587.
28. Raucy JL, Mueller L, Duan K, Allen SW, Strom S, and Lasker JM (2002) Expression and induction of CYP2C P450 enzymes in primary cultures of human hepatocytes. J Pharmacol Exp Ther 302:475-482.
29. Sandoval TM, Grettenberger HM, and Zhang KE (1998) Metabolism of nelfinavir mesylate and HIV-1 protease inhibitor by human liver microsomes and recombinant human isoforms, in XII Annual Meeting and Exposition of the American Association of Pharmaceutical Scientists; November 1998, San Francisco. Abstract 1096. American Association of Pharmaceutical Scientists, Arlington, VA.
30. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, and Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76-85.
31. Tebas P and Powderly WG (2000) Nelfinavir mesylate. Expert Opin Pharmacother 1:1429-1440.
32. Vella S and Floridia M (1998) Saquinavir. Clinical pharmacology and efficacy. Clin Pharmacokinet 34:189-201.
33. Walsh JC, Jones CD, Barnes EA, Gazzard BG, and Mitchell SM (1998) Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors. AIDS 12:613-618.
34. Wu EY, Sandoval TM, Lee CA, Zhang K, Liang BH, and Shetty BV (1996) In vitro metabolism studies with the HIV-1 protease inhibitor, Viracept (AG1343). ISSX Proc 10:326.
35. Zhang KE, Wu E, Patick AK, Kerr B, Zorbas M, Lankford A, Kobayashi T, Maeda Y, Shetty B, and Webber S (2001) Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma and antiviral activities. Antimicrob Agents Chemother 45:1086-1093.