10027828

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3

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 x 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 the Cmax 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 the Cmax and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by approximately 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 approximately 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.

eng

IM

MEDLINE

0022-3565

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NLM

928-37

pubmed-meshheading:10027828-Animals, pubmed-meshheading:10027828-Antineoplastic Agents, pubmed-meshheading:10027828-Area Under Curve, pubmed-meshheading:10027828-Brain Neoplasms, pubmed-meshheading:10027828-Cyclophosphamide, pubmed-meshheading:10027828-Cytochrome P-450 Enzyme System, pubmed-meshheading:10027828-Dexamethasone, pubmed-meshheading:10027828-Disease Models, Animal, pubmed-meshheading:10027828-Enzyme Induction, pubmed-meshheading:10027828-Female, pubmed-meshheading:10027828-Gliosarcoma, pubmed-meshheading:10027828-Half-Life, pubmed-meshheading:10027828-Hydroxylation, pubmed-meshheading:10027828-Ifosfamide, pubmed-meshheading:10027828-Liver, pubmed-meshheading:10027828-Male, pubmed-meshheading:10027828-Microsomes, Liver, pubmed-meshheading:10027828-Phenobarbital, pubmed-meshheading:10027828-Rats, pubmed-meshheading:10027828-Rats, Inbred F344, pubmed-meshheading:10027828-Troleandomycin

In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity.

Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't