THE MULTIDRUG-RESISTANCE MODULATOR VALSPODAR (PSC-833) IS METABOLIZEDBY HUMAN CYTOCHROME-P450 3A - IMPLICATIONS FOR DRUG-DRUG INTERACTIONSAND PHARMACOLOGICAL ACTIVITY OF THE MAIN METABOLITE

The metabolism of valspodar (PSC 833; PSC), which is developed as a mu ltidrug resistance-reversing agent, was investigated to assess the pot ential for drug-drug interactions and the pharmacological activity of major metabolites. The primary metabolites of PSC produced by human li ver microsomes were monohydroxylated, as revealed by LC/MS. The major site of hydroxylation was at amino acid 9, resulting in M9, as determi ned by cochromatography with synthetic M9. Dihydroxylated and N-demeth ylated metabolites were also detected. PSC metabolism in two human liv ers exhibited K-M values of 1.3-2.8 mu M. The intrinsic clearance was 9-36 ml/min/kg of body weight. PSC biotransformation was cytochrome P4 50 (CYP or P450) 3A dependent, based on chemical inhibition and on met abolism by Chinese hamster ovary cells expressing CYP3A. Ketoconazole was a competitive inhibitor (K-i = 0.01-0.04 mu M). The inhibition by 27 compounds, including four antineoplastic agents, corresponded to th e inhibitory potentials of these compounds toward CYP3A. For vinblasti ne, paclitaxel, doxorubicin, and etoposide, the IC50 values were 5, 12 , 20, and 150 mu M, respectively. M9 was also an inhibitor, with a low er apparent affinity for CYP3A (IC50 = 21 mu M), compared with that of PSC. M9 was also less active as a multidrug resistance-reversing agen t. M9 demonstrated low potency in sensitizing resistant cells to pacli taxel and was a poor inhibitor of rhodamine-123 efflux from paclitaxel -resistant cells. In addition, compared with PSC, a higher concentrati on of M9 was needed to compete with the photoaffinity labeling of P-gl ycoprotein, Conversely, PSC inhibited only reactions catalyzed by CYP3 A, including cyclosporine A metabolism (IC50 = 6.5 mu M) and p-hydroxy phenyl-C3'-paclitaxel formation (K-i = 1.2 mu M). Thus, PSC behaves in a manner very similar to that of other cyclosporines, and a comparabl e drug-drug interaction profile is expected.