PHARMACOKINETIC CHANGES OF M1, M2, M3 AND M4 AFTER INTRAVENOUS ADMINISTRATION OF A NEW ANTHRACYCLINE, DA-125, TO RATS PRETREATED WITH PHENOBARBITAL, 3-METHYLCHOLANTHRENE, CHLORAMPHENICOL, OR SKF-525A

The pharmacokinetics of M1-M4, the metabolites of a new anthracycline antineoplastic agent, DA-125, were compared after intravenous (IV) adm inistration of DA-125, 15 mg kg(-1), to rats pretreated with enzyme in ducers, such as phenobarbital (PET, n = 14) and 5-methylcholanthrene ( MCT, n = 15), or enzyme inhibitors, such as SKF-525A (SKT, n = 11) and chloramphenicol (CMT, n = 15), and to their control rats (n = 15 for PBC, CMC or SKC, and n = 11 for MCC). After IV administration of DA-12 5, the plasma concentrations of both M1 and M2 declined slowly from 1 to 2 h onwards to 8 h in all groups of rats due to the continuous form ation of M2 from M1. The AUC(0-8) of M1 (47.1 versus 7.85 mu g min mL( -1)) and M2 (20.7 versus 44.3 mu g min mL(-1)) decreased significantly in the PBT group compared to those in the PBC group. However, the cor responding value of only M1 (74.6 versus 89.9 mu g min mL(-1)) decreas ed significantly in the MCT group. The above data indicate that metabo lism of M1 is increased by pretreatment with both PB and 3-MC, and tha t of M2 with PB, but not with 3-MC. The AUC(0-8 h) of both M1 (126 ver sus 78.5 mu g min mL(-1)) and M2 (69.2 versus 44.3 mu g min mL(-1)) in creased significantly in the SKT group compared to the SKC group. Howe ver, the corresponding values were not significantly different between CMC and CMT groups. The above data indicate that the metabolism of bo th M1 and M2 is inhibited by pretreatment with SKF-525A, but not with CM. (C) 1998 John Wiley & Sons, Ltd.