![[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}
|
|
|
|
|
||
M Murray, AM Butler and I Stupans
Department of Medicine, University of Sydney, Westmead Hospital, Australia.
The prodrugs cyclophosphamide (CP) and ifosfamide (IF) are oxidized by hepatic cytochrome P450 (P450) to the active cytotoxic species, phosphoramide mustard. Acrolein (prop-2-enal) is also formed during CP and IF activation in rat liver and has been associated with P450 destruction. Analogous inactivation of human liver P450s by CP or IF could lead to pharmacokinetic interactions with coadministered drugs. The present study investigated the susceptibilities of human hepatic P450s to inhibition and inactivation by CP and IF in vitro. Unlike the situation in rat liver microsomes, total P450 was not decreased after incubation of CP or IF with NADPH and human fractions. However, CP and IF inhibited testosterone 6 beta-hydroxylation mediated by P450s 3A but not P450 1A2-dependent 7-ethylresorufin O-deethylation, P450 2C- dependent tolbutamide methyl hydroxylation or P450 2E1-mediated N- nitrosodimethylamine N-demethylation. Kinetic analysis indicated that the drugs were reversible (competitive) inhibitors of testosterone 6 beta-hydroxylation (Km, 94 +/- 8 microM) in human liver microsomes (KiS, 510 +/- 20 microM and 490 +/- 40 microM for CP and IF, respectively). Time-dependent intensification of the inhibition of the activity by CP or IF did not occur; this supports the observation that P450 was refractory to inactivation. The rates of acrolein formation from CP and IF in human hepatic microsomes (0.76 +/- 0.23 and 0.19 +/- 0.07 nmol min-1 mg-1 of protein, respectively) were only 18% and 10% of the rates estimated in fractions from untreated rat liver (4.20 +/- 0.04 and 1.96 +/- 0.12 nmol min-1 mg-1 of protein, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
This article has been cited by other articles:
|
|
 |
|
  R. Obligacion, M. Murray, and I. Ramzan Drug-Metabolizing Enzymes and Transporters: Expression in the Human Prostate and Roles in Prostate Drug Disposition J Androl, March 1, 2006; 27(2): 138 - 150. [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Walsky and R. S. Obach VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S H Lam and R. J Ignoffo A guide to clinically relevant drug interactions in oncology Journal of Oncology Pharmacy Practice, June 1, 2003; 9(2-3): 45 - 85. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Hamaoka, Y. Oda, I. Hase, and A. Asada Cytochrome P4502B6 and 2C9 do not metabolize midazolam: kinetic analysis and inhibition study with monoclonal antibodies Br. J. Anaesth., April 1, 2001; 86(4): 540 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Bernard and E. Bruera Drug Interactions in Palliative Care J. Clin. Oncol., April 1, 2000; 18(8): 1780 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sutton, A. M. Butler, L. Nadin, and M. Murray Role of CYP3A4 in Human Hepatic Diltiazem N-Demethylation: Inhibition of CYP3A4 Activity by Oxidized Diltiazem Metabolites J. Pharmacol. Exp. Ther., July 1, 1997; 282(1): 294 - 300. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
