COMPARISON OF PHARMACOKINETICS OF M1, M2, M3, AND M4 AFTER INTRAVENOUS ADMINISTRATION OF DA-125 OR ME2303 TO MICE AND RATS, NEW ADRIAMYCIN ANALOGS CONTAINING FLUORINE

The pharmacokinetics of M1, M2, M3, and/or M4 were compared after intr avenous (iv) administration of DA-125 and/or ME2303 to mice (25 mg kg( -1)) and rats (5, 10, 20, 30, and 40 mg kg(-1)). The mean plasma conce ntrations of M1 were detected up to 8 h after iv administration of bot h DA-125 and ME2303 to mice, and were significantly higher for DA-125 than ME2303; this resulted in a considerably greater AUC (303 against 148 mu g min mL(-1)) and a considerably slower CL of M1 (69 . 3 agains t 136 mL min(-1) kg(-1)) after iv administration of DA-125. The MRT (3 71 against 189 min) and CL(NR) Of M1 (68 . 7 against 136 mL min(-1) kg (-1)) were considerably greater and slower, respectively, after iv adm inistration of DA-125. The mean plasma concentrations of M2 were detec ted up to 8 and 4h after iv administration of DA-125 and ME2303, respe ctively, to mice and were significantly higher for DA-125 than ME2303, resulting in a considerably greater AUC of M2 (148 against 27 . 1 mu g min mL(-1)) after iv administration of DA-125. The mean plasma conce ntrations of M3, being the lowest among M1-M4, were detected only up t o 15 min after iv administration of both DA-125 and ME2303 to mice, an d were comparable after iv adminstration of DA-125 and ME2303 to mice. The mean plasma concentrations of M4 were detected up to 8 h after iv administration of both DA-125 and ME2303 to mice, and were higher aft er iv administration of DA-125 than ME2303, resulting in a considerabl y greater AUC of M4 (197 against 61 . 9 mu g min mL(-1)) after iv admi nistration of DA-125. Similar results on M1 and M2 were also obtained from rats: the mean plasma concentrations of both M1 and M2 were signi ficantly higher after iv administration of DA-125, 10 mg kg(-1), than after ME2303. The plasma concentrations of M1, M2, and M4, and hence t heir AUCs, were significantly higher after iv administration of DA-125 , 5, 10, 20, 30, and 40 mg kg(-1), to rats than after ME2303: the mean plasma concentrations of M2, approximately 0 . 1-0 . 4 mu g mL(-1), w ere maintained from 30 min to 8-10 h after iv administration of DA-125 , 20, 30, and 40 mg kg(-1), to rats; the plasma concentrations of M3 w ere the lowest among M1-M4 at all DA-125 doses; and those of M1 and M4 were maintained for a long period of time. However, after iv administ ration of M2, 5 mg kg(-1), to rats, the mean plasma concentrations of M2 were detected up to 60 min with a mean terminal half-life of only 3 8 . 8 min, and the concentrations of M3 were negligible. After iv admi nistration of M3, 5 mg kg(-1), to rats, the mean plasma concentrations of M3 were detected up to 15 min; the plasma concentrations of M4, re aching their peak at 5 min, decayed more slowly and were higher than t hose of M3. The AUC of M4 after iv administration of M3, 5 mg kg(-1), was comparable to that after iv administration of M4, 5 mg kg(-1), to rats, suggesting that M4 is formed fast and almost completely from M3. M1 was not detected in plasma after iv administration of either M2 or M3 to rats. After iv administration of M4, 5 mg kg(-1), to rats, the mean plasma concentrations of M4 decayed fast with a mean terminal hal f-life of 43 . 9 min and neither M2 nor M3 were detected in plasma. Th e following disposition mechanisms for M1, M2, M3, and M4 after iv adm inistration of DA-125 to rats could be obtained from the above data: ( i) the maintenance of plasma concentrations of M2 for a longer period of time after iv administration of DA-125 than those after iv administ ration of M2 could be due to the continuous formation of M2 from M1; ( ii) the lowest plasma concentrations of M3 among M1-M4 after iv admini stration of DA-125 could be due to the fast and almost complete format ion of M4 from M3 as soon as M3 is formed from M1, and not due to the fast renal excretion of unchanged M3; (iii) M4 was exclusively and con tinuously formed from M3 and the formation of M4 from M2 was negligibl e; and (iv) reversible metabolism among M1-M4 did not take place The f ollowing results could also be obtained after iv administration of DA- 125 or ME2303 to mice and rats: (i) the lower plasma concentrations of M1 after iv administration of ME2303 than of DA-125 could be due to t he greater biliary excretion of unchanged ME2303 (approximately 30% of iv dose) than unchanged DA-125 and (ii) the lower plasma concentratio ns of M2 and M4 after iv administration of ME2303 than after DA-125 co uld be due to lower plasma concentrations of M1 and hence less formati on of both M2 and M4 from M1. Liver showed the highest metabolic activ ity for M1 and a considerable amount of M1 was also metabolized in the kidney after 30 min incubation of 50 mu g of DA-125 in 9000g supernat ant fraction of rat tissue homogenates. The mean amount of M1 remainin g per gram of tissue, the total amount of M1 remaining in whole tissue , and the tissue to plasma ratio of M1 were significantly higher in th e heart, lung, large intestine, and kidney at 15 min after iv administ ration of DA-125, 25 mg kg(-1), to mice than after ME2303. M1, the act ive antineoplastic moiety of DA-125, had higher affinity for the lung after iv administration of DA-125 to mice than after ME2303, indicatin g that lung tumours could be subjected to a greater exposure to M1 aft er iv administration of DA-125 than ME2303. The 24 h biliary excretion of M1 was significantly greater after the iv administration of ME2303 than after DA-125 (344 against 79 . 3 mu g). However, reversed result s were obtained for M2 (267 against 467 mu g). M3 and M4 were under th e detection limit in the bile sample after iv administration of either DA-125 or ME2303.