![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Institute for Biomedical Research, Hackensack University Medical Center, Hackensack, New Jersey (V.N.H., J.M.L.); and California Toxicology Research Institute, Carlsbad, California (J.L.R.)
Antiretroviral therapy for human immunodeficiency virus (HIV) infection includes treatment with both reverse transcriptase inhibitors and protease inhibitors, which markedly suppress viral replication and circulating HIV RNA levels. Cytochrome P450 (P450) enzymes in human liver, chiefly CYP3A4, play a pivotal role in protease inhibitor biotransformation, converting these agents to largely inactive metabolites. However, the protease inhibitor nelfinavir (Viracept) is metabolized mainly to nelfinavir hydroxy-t-butylamide (M8), which exhibits potent antiviral activity, and to other minor products (termed M1 and M3) that are inactive. Since indirect evidence suggests that CYP2C19 underlies M8 formation, we examined the role of this inducible, polymorphic P450 enzyme in nelfinavir t-butylamide hydroxylation by human liver. Rates of microsomal M8 formation were 50.6 ± 28.3 pmol of product formed/min/nmol P450 (n = 5 subjects), whereas kinetic analysis of the reaction revealed a KM of 21.6 µM and a Vmax of 24.6 pmol/min/nmol P450. In reconstituted systems, CYP2C19 catalyzed nelfinavir t-butylamide hydroxylation at a turnover rate of 2.2 min-1, whereas CYP2C9, CYP2C8, and CYP3A4 were inactive toward nelfinavir. Polyclonal anti-CYP2C9 (cross-reactive with CYP2C19) and monoclonal anti-CYP2C19 completely inhibited microsomal M8 production, whereas monoclonal CYP2C9 and polyclonal CYP3A4 antibodies were without effect. Similarly, the CYP2C19 substrate omeprazole strongly inhibited (75%) hepatic nelfinavir t-butylamide hydroxylation at a concentration of only 12.5 µM. Our study shows that CYP2C19 underlies formation in human liver of M8, a bioactive nelfinavir metabolite. The inducibility of CYP2C19 by agents (e.g., rifampicin) often taken concurrently with nelfinavir, together with this P450's known polymorphic nature, may thus be important determinants of nelfinavir's antiviral potency.
This article has been cited by other articles:
|
|
 |
|
  B. Damle, C. Fosser, K. Ito, A. Tran, P. Clax, H. Uderman, and P. Glue Effects of Standard and Supratherapeutic Doses of Nelfinavir on Cardiac Repolarization: A Thorough QT Study J. Clin. Pharmacol., March 1, 2009; 49(3): 291 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Estes, K. H. Busse, and S. R. Penzak Pharmacogenetic Considerations in the Management of HIV Infection Journal of Pharmacy Practice, June 1, 2007; 20(3): 234 - 245. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Stocker, C. Herzmann, A. Breske, G. Kruse, M. Berger, H. Schulbin, A. Hill, J. Steinmuller, M. Becker, K. Arasteh, et al. Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration J. Antimicrob. Chemother., March 1, 2007; 59(3): 560 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Damle, D. Hewlett Jr, P.-H. Hsyu, M. Becker, and A. Petersen Pharmacokinetics of nelfinavir in subjects with hepatic impairment. J. Clin. Pharmacol., November 1, 2006; 46(11): 1241 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Garazzino, M. Tettoni, A. Calcagno, A. D'Avolio, S. Bonora, and G. D. Perri Ritonavir-dependent fluconazole boosting of nelfinavir: a report of three cases J. Antimicrob. Chemother., August 1, 2006; 58(2): 483 - 485. [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
