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Vol. 288, Issue 3, 928-937, March 1999
Division of Cell and Molecular Biology, Department of Biology,
Boston University, Boston, Massachusetts
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 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
~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.
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