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Research ArticleArticle

In Vivo Modulation of Alternative Pathways of P-450-Catalyzed Cyclophosphamide Metabolism: Impact on Pharmacokinetics and Antitumor Activity

Li J. Yu, Pernille Drewes, Katja Gustafsson, Etienne G. C. Brain, Jodi E. D. Hecht and David J. Waxman
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 928-937;
Li J. Yu
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Pernille Drewes
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Katja Gustafsson
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Etienne G. C. Brain
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Jodi E. D. Hecht
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David J. Waxman
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Abstract

The widely used anticancer prodrug cyclophosphamide (CPA) is activated in liver by a 4-hydroxylation reaction primarily catalyzed by cytochrome P-4502B and P-4502C enzymes. An alternative metabolic pathway involves CPA N-dechloroethylation to yield chloroacetaldehyde (CA), a P-4503A-catalyzed deactivation/neurotoxication reaction. The in vivo modulation of these alternative, competing pathways of P-450 metabolism was investigated in pharmacokinetic studies carried out in the rat model. Peak plasma concentrations (Cmax) for 4-OH-CPA and CA were increased by 3- to 4-fold, and apparent plasma half-lives of both metabolites were correspondingly shortened in rats pretreated with phenobarbital (PB), an inducer of P-4502B and P-4503A enzymes. However, PB had no net impact on the extent of drug activation or its partitioning between these alternative metabolic pathways, as judged from AUC values (area-under-the-plasma concentration × time curve) for 4-OH-CPA and CA. The P-4503A inhibitor troleandomycin (TAO) decreased plasma Cmax and AUC of CA (80–85% decrease) without changing theCmax or AUC of 4-OH-CPA in uninduced rats. In PB-induced rats, TAO decreased AUCCA by 73%, whereas it increased AUC4-OH-CPA by 93%. TAO thus selectively suppresses CPA N-dechloroethylation, thereby increasing the availability of drug for P-450 activation via 4-hydroxylation. By contrast, dexamethasone, a P-4503A inducer and antiemetic widely used in patients with cancer, stimulated large, undesirable increases in theCmax and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by ∼60%. Tumor excision/in vitro colony formation and tumor growth delay assays using an in vivo 9L gliosarcoma solid tumor model revealed that TAO suppression of CPA N-dechloroethylation could be achieved without compromising the antitumor effect of CPA. The combination of PB with TAO did not, however, enhance the antitumor activity of CPA, despite the ∼2-fold increase in AUC4-OH-CPA, suggesting that other PB-inducible activities, such as aldehyde dehydrogenase, may counter this increase through enhanced deactivation of the 4-hydroxy metabolite. Together, these studies demonstrate that the P-4503A inhibitor TAO can be used to effectively modulate CPA metabolism and pharmacokinetics in vivo in a manner that decreases the formation of toxic metabolites that do not contribute to antitumor activity.

Footnotes

  • Send reprint requests to: Dr. David J. Waxman, Department of Biology, Boston University, 5 Cummington St., Boston, MA 02215. E-mail: djw{at}bio.bu.edu

  • ↵1 This work was supported in part by National Institutes of Health Grant CA49248 (D.J.W.). K.G. and P.D. contributed equally to this study as part of their Masters dissertation research for the Royal Danish School of Pharmacy, Copenhagen. E.G.C.B. received fellowship support from L’Association Pour la Recherche sur le Cancer.

  • Abbreviations:
    P-450 or CYP
    cytochrome P-450
    CPA
    cyclophosphamide
    4-OH-CPA
    4-hydroxy-cyclophosphamide
    CA
    chloroacetaldehyde
    IFA
    ifosfamide
    4-OH-IFA
    4-hydroxy-ifosfamide
    PB
    phenobarbital
    TAO
    troleandomycin
    DEX
    dexamethasone
    UT
    untreated (uninduced) rat treatment group
    AUC
    area-under-the-curve, plasma X concentration
    Cmax
    peak plasma concentration
    Tmax
    time ofCmax
    Cpl
    plasma concentration
    T1/2
    apparent half-life, which reflects both the rate of metabolite formation and the intrinsic rate of metabolite elimination
    • Received June 11, 1998.
    • Accepted September 29, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

In Vivo Modulation of Alternative Pathways of P-450-Catalyzed Cyclophosphamide Metabolism: Impact on Pharmacokinetics and Antitumor Activity

Li J. Yu, Pernille Drewes, Katja Gustafsson, Etienne G. C. Brain, Jodi E. D. Hecht and David J. Waxman
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 928-937;

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Research ArticleArticle

In Vivo Modulation of Alternative Pathways of P-450-Catalyzed Cyclophosphamide Metabolism: Impact on Pharmacokinetics and Antitumor Activity

Li J. Yu, Pernille Drewes, Katja Gustafsson, Etienne G. C. Brain, Jodi E. D. Hecht and David J. Waxman
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 928-937;
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