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In Vivo Modulation of Alternative Pathways of P-450-Catalyzed Cyclophosphamide Metabolism: Impact on Pharmacokinetics and Antitumor Activity
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 deact...
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Published in: | The Journal of pharmacology and experimental therapeutics 1999-03, Vol.288 (3), p.928 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | 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 ( C max ) 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 à time curve) for 4-OH-CPA and CA. The P-4503A inhibitor troleandomycin (TAO) decreased
plasma C max and AUC of CA (80â85% decrease) without changing the C max or AUC of 4-OH-CPA in uninduced rats. In PB-induced rats, TAO decreased AUC CA by 73%, whereas it increased AUC 4-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 the C max and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by â¼60%. 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 â¼2-fold increase in AUC 4-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. |
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ISSN: | 0022-3565 1521-0103 |