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Vol. 26, Issue 8, 802-811, August 1998
Preclinical Safety (V.F., A.R.-G., F.H., R.T., C.H., A.E.M.V.) and
Oncology Research Group (D.C.), Novartis Pharmaceuticals
The metabolism of valspodar (PSC 833; PSC), which is developed as a
multidrug resistance-reversing agent, was investigated to assess the
potential for drug-drug interactions and the pharmacological activity
of major metabolites. The primary metabolites of PSC produced by human
liver microsomes were monohydroxylated, as revealed by LC/MS. The major
site of hydroxylation was at amino acid 9, resulting in M9, as
determined by cochromatography with synthetic M9. Dihydroxylated
and N-demethylated metabolites were also detected. PSC
metabolism in two human livers exhibited
KM values of 1.3-2.8 µM. The intrinsic
clearance was 9-36 ml/min/kg of body weight. PSC biotransformation was
cytochrome P450 (CYP or P450) 3A dependent, based on chemical
inhibition and on metabolism by Chinese hamster ovary cells expressing
CYP3A. Ketoconazole was a competitive inhibitor (Ki = 0.01-0.04 µM). The inhibition by
27 compounds, including four antineoplastic agents, corresponded to the
inhibitory potentials of these compounds toward CYP3A. For vinblastine,
paclitaxel, doxorubicin, and etoposide, the
IC50 values were 5, 12, 20, and 150 µM,
respectively. M9 was also an inhibitor, with a lower
apparent affinity for CYP3A (IC50 = 21 µM),
compared with that of PSC. M9 was also less active as a multidrug
resistance-reversing agent. M9 demonstrated low potency in
sensitizing resistant cells to paclitaxel and was a poor inhibitor of
rhodamine-123 efflux from paclitaxel-resistant cells. In addition,
compared with PSC, a higher concentration of M9 was needed to
compete with the photoaffinity labeling of P-glycoprotein. Conversely,
PSC inhibited only reactions catalyzed by CYP3A, including cyclosporine
A metabolism (IC50 = 6.5 µM) and
p-hydroxyphenyl-C3'-paclitaxel formation
(Ki = 1.2 µM). Thus, PSC behaves in a
manner very similar to that of other cyclosporines, and a comparable
drug-drug interaction profile is expected.
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