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 inhibitor of angiogenesis, and several commonly used anticancer agents, such as cyclophosphamide, taxol, and minocycline, were investigated in vitro using primary cultured hepatocytes and microsomes of rhesus monkeys. After incubation of hepatocytes with 5 microM [3H]TNP-470, rapid and extensive formation of six metabolites was observed, with M-II and M-IV being the predominant metabolites. After 30 min of incubation in the presence of 250 microM cyclophosphamide, concentrations of unchanged TNP-470 and M-IV were increased with values of 1.00 +/- 0.02 and 1.49 +/- 0.01 microM compared with control values of 0.67 +/- 0.09 (p =.02), 1.39 +/- 0. 03 microM (p <.01), respectively. In contrast, the concentration of M-II was substantially decreased from 1.69 +/- 0.86 to 1.02 +/- 0.16 microM (p =.01). Combination of taxol with TNP-470 led to a 50% decrease of M-II levels (p <.01), whereas unchanged TNP-470 and 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 microM minocycline had no effect on TNP-470 metabolism in monkey hepatocytes. In vitro studies with isolated monkey liver microsomes confirmed these drug-drug metabolic interactions detected at the cellular level. A detailed understanding of the potential drug interactions in TNP-470 metabolism occurring with taxol or cyclophosphamide is critical to fully elucidate the potentiation of the antitumor activity observed in vivo after coadministration of these two agents with TNP-470.