Metabolic drug interactions between angiogenic inhibitor, TNP-470 and anticancer agents in primary cultured hepatocytes and microsomes

The potential metabolic drug interactions between TNP-470, a potent inhibit or of angiogenesis, and several commonly used anticancer agents, such as cy clophosphamide, taxol, and minocycline, were investigated in vitro using pr imary cultured hepatocytes and microsomes of rhesus monkeys. After incubati on of hepatocytes with 5 mu M [H-3]TNP-470, rapid and extensive formation o f six metabolites was observed, with M-II and M-IV being the predominant me tabolites. After 30 min of incubation in the presence of 250 mu M cyclophos phamide, concentrations of unchanged TNP-470 and M-IV were increased with v alues of 1.00 +/- 0.02 and 1.49 +/- 0.01 mu M compared with control values of 0.67 +/- 0.09 (p = .02), 1.39 +/- 0.03 mu M (p < .01), respectively. In contrast, the concentration of M-II was substantially decreased from 1.69 /- 0.86 to 1.02 +/- 0.16 mu M (p = .01). Combination of taxol with TNP-470 led to a 50% decrease of M-II levers (p < .01), whereas unchanged TNP-470 a nd M-IV levels were increased by at least 2.5-fold compared with control (p = .08 and 0.01). Exposure of cells to TNP-470 with 250 mu M minocycline ha d no effect on TNP-470 metabolism in monkey hepatocytes. In vitro studies w ith isolated monkey liver microsomes confirmed these drug-drug metabolic in teractions detected at the cellular level. A detailed understanding of the potential drug interactions in TNP-470 metabolism occurring with taxol or c yclophosphamide is critical to fully elucidate the potentiation of the anti tumor activity observed in vivo after coadministration of these two agents with TNP-470.