This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An author's correction has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, K. E.
Right arrow Articles by Webber, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, K. E.
Right arrow Articles by Webber, S.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2001, p. 1086-1093, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1086-1093.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

Kanyin E. Zhang,1,* Ellen Wu,1 Amy K. Patick,1 Bradley Kerr,1 Mark Zorbas,1 Angela Lankford,1 Takuo Kobayashi,2 Yuki Maeda,2 Bhasker Shetty,1 and Stephanie Webber1

Pfizer Global Research and Development, La Jolla, California,1 and Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka 569, Japan2

Received 3 July 2000/Returned for modification 22 October 2000/Accepted 23 December 2000

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (Ki = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3'-methoxy-4'-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 µM and the M8 concentrations ranged from 0.55 to 1.96 µM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 µM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

* Corresponding author. Present address: Drug Metabolism and Pharmacokinetics, Merck Research Laboratories-San Diego, 505 Coast Blvd. South, Suite 300, La Jolla, CA 92037. Phone: (858) 452-5892, ext. 488. Fax: (858) 452-9279. E-mail: kanyin_zhang{at}merck.com.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1086-1093, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1086-1093.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Zhang, H., Wu, X., Naraharisetti, S. B., Chung, F., Whittington, D., Mirfazaelian, A., Unadkat, J. D. (2009). Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina. J. Pharmacol. Exp. Ther. 330: 586-595 [Abstract] [Full Text]  
  • Zhang, H., Wu, X., Chung, F., Naraharisetti, S. B., Whittington, D., Mirfazaelian, A., Unadkat, J. D. (2009). As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina. J. Pharmacol. Exp. Ther. 329: 1016-1022 [Abstract] [Full Text]  
  • Mahungu, T W, Johnson, M A, Owen, A, Back, D J (2009). The impact of pharmacogenetics on HIV therapy. Int J STD AIDS 20: 145-151 [Abstract] [Full Text]  
  • Damle, B., Fosser, C., Ito, K., Tran, A., Clax, P., Uderman, H., Glue, P. (2009). Effects of Standard and Supratherapeutic Doses of Nelfinavir on Cardiac Repolarization: A Thorough QT Study. J Clin Pharmacol 49: 291-300 [Abstract] [Full Text]  
  • Parker, A. J., Houston, J. B. (2008). Rate-Limiting Steps in Hepatic Drug Clearance: Comparison of Hepatocellular Uptake and Metabolism with Microsomal Metabolism of Saquinavir, Nelfinavir, and Ritonavir. Drug Metab. Dispos. 36: 1375-1384 [Abstract] [Full Text]  
  • Damle, B., Hewlett, D. Jr, Hsyu, P.-H., Becker, M., Petersen, A. (2006). Pharmacokinetics of nelfinavir in subjects with hepatic impairment.. J Clin Pharmacol 46: 1241-1249 [Abstract] [Full Text]  
  • Hirt, D., Treluyer, J.-M., Jullien, V., Firtion, G., Chappuy, H., Rey, E., Pons, G., Mandelbrot, L., Urien, S. (2006). Pregnancy-related effects on nelfinavir-m8 pharmacokinetics: a population study with 133 women.. Antimicrob. Agents Chemother. 50: 2079-2086 [Abstract] [Full Text]  
  • Mathias, A. A., Maggio-Price, L., Lai, Y., Gupta, A., Unadkat, J. D. (2006). Changes in Pharmacokinetics of Anti-HIV Protease Inhibitors during Pregnancy: The Role of CYP3A and P-glycoprotein. J. Pharmacol. Exp. Ther. 316: 1202-1209 [Abstract] [Full Text]  
  • Payen, S., Faye, A., Compagnucci, A., Giaquinto, C., Gibbs, D., Gomeni, R., Bressolle, F., Jacqz-Aigrain, E. (2005). Bayesian Parameter Estimates of Nelfinavir and Its Active Metabolite, Hydroxy-tert-Butylamide, in Infants Perinatally Infected with Human Immunodeficiency Virus Type 1. Antimicrob. Agents Chemother. 49: 525-535 [Abstract] [Full Text]  
  • Regazzi, M., Maserati, R., Villani, P., Cusato, M., Zucchi, P., Briganti, E., Roda, R., Sacchelli, L., Gatti, F., Delle Foglie, P., Nardini, G., Fabris, P., Mori, F., Castelli, P., Testa, L. (2005). Clinical Pharmacokinetics of Nelfinavir and Its Metabolite M8 in Human Immunodeficiency Virus (HIV)-Positive and HIV-Hepatitis C Virus-Coinfected Subjects. Antimicrob. Agents Chemother. 49: 643-649 [Abstract] [Full Text]  
  • Ernest, C. S. II, Hall, S. D., Jones, D. R. (2005). Mechanism-Based Inactivation of CYP3A by HIV Protease Inhibitors. J. Pharmacol. Exp. Ther. 312: 583-591 [Abstract] [Full Text]  
  • Hirani, V. N., Raucy, J. L., Lasker, J. M. (2004). CONVERSION OF THE HIV PROTEASE INHIBITOR NELFINAVIR TO A BIOACTIVE METABOLITE BY HUMAN LIVER CYP2C19. Drug Metab. Dispos. 32: 1462-1467 [Abstract] [Full Text]  
  • Bergshoeff, A. S, Wolfs, T. F., Geelen, S. P., Burger, D. M (2003). Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 During Rifampin Use. The Annals of Pharmacotherapy 37: 521-525 [Abstract] [Full Text]  
  • Piliero, P. J. (2003). Early Factors in Successful Anti-HIV Treatment. J Int Assoc Physicians AIDS Care (Chic Ill) 2: 10-20 [Abstract]  
  • Savolainen, J., Edwards, J. E., Morgan, M. E., McNamara, P. J., Anderson, B. D. (2002). Effects of a P-Glycoprotein Inhibitor on Brain and Plasma Concentrations of Anti-Human Immunodeficiency Virus Drugs Administered in Combination in Rats. Drug Metab. Dispos. 30: 479-482 [Abstract] [Full Text]  
  • Hsyu, P.-H., Schultz-Smith, M. D., Lillibridge, J. H., Lewis, R. H., Kerr, B. M. (2001). Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Simvastatin. Antimicrob. Agents Chemother. 45: 3445-3450 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»