RT Journal Article
SR Electronic
T1 The Multidrug Resistance Modulator Valspodar (PSC 833) Is Metabolized by Human Cytochrome P450 3A
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 802
OP 811
VO 26
IS 8
A1 Volker Fischer
A1 Alicia Rodríguez-Gascón
A1 Francis Heitz
A1 Ronald Tynes
A1 Christian Hauck
A1 Dalia Cohen
A1 Alison E. M. Vickers
YR 1998
UL http://dmd.aspetjournals.org/content/26/8/802.abstract
AB 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 exhibitedKM 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) andp-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. The American Society for Pharmacology and Experimental Therapeutics