INTERACTIONS BETWEEN CYCLOPHOSPHAMIDE AND ADRIAMYCIN METABOLISM IN RATS

Abstract

Rat liver microsomes under anaerobic conditions metabolize adriamycin (ADM) [antineoplastic agent] to 7-deoxyadriamycinol aglycone and 7-deoxyadriamycin aglycone. The metabolism of ADM and the concentration of cytochrome P-450 were not affected by preincubation with 2.76 mM cyclophosphamide [antineoplastic agent]. After preincubation of microsomes with 0.2 mM 4-hydroperoxycyclophosphamide, a prodrug of 4-hydroxycyclophosphamide, there was complete denaturation of the cytochrome P-450, and 22.8% inhibition of NADPH-cytochrome P-450 reductase. Under these conditions, the degradation of ADM was delayed (area under the concentration vs. time curve in .mu.mol .times. min: 15.6 .+-. 2.4 for the controls, and 59.8 .+-. 7.3 in the presence of 4-hydroperoxycyclophosphamide, P .ltoreq. 0.005), 7-deoxyadriamycin aglycone increased progressively to reach a plateau at 20 min instead of showing a peak at 2 min and the formation of 7-deoxyadriamycinol aglycone was reduced. Microsomes from animals pretreated with cyclophosphamide (180 mg/kg i.p. once 4 days before sacrifice) showed a 24.0% reduction of NADPH-cytochrome P-450 reductase activity (P .ltoreq. 0.02). This was accompanied by a decreased formation of 7-deoxyadriamycinol aglycone during the first 20 min of incubation (area under the concentration vs. time curve in .mu.mol .times. min: 68.0 .+-. 15.7 in the controls, and 25.6 .+-. 3.1 in the treated animals, P .ltoreq. 0.005), whereas the formation of 7-deoxyadriamycin aglycone was not affected. These data indicate an interaction between the metabolism of cyclophosphamide and ADM in rats.