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

Autor: Hyun J. Shim, Woo I. Lee, Won B. Kim, Eun J. Yoon, Junnick Yang, Myung Gyoon Lee, Sang D. Lee
Rok vydání: 1996
Předmět:
Zdroj: Biopharmaceutics & Drug Disposition. 17:373-420
ISSN: 1099-081X
0142-2782
Popis: The pharmacokinetics of M1, M2, M3, and/or M4 were compared after intravenous (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 concentrations of M1 were detected up to 8 h after iv administration of both 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 μg min mL−1) and a considerably slower CL of M1 (69·3 against 136 mL min−1 kg−1) after iv administration of DA-125. The MRT (371 against 189 min) and CLNR of M1 (68·7 against 136 mL min−1 kg−1) were considerably greater and slower, respectively, after iv administration of DA-125. The mean plasma concentrations of M2 were detected up to 8 and 4 h after iv administration of DA-125 and ME2303, respectively, to mice and were significantly higher for DA-125 than ME2303, resulting in a considerably greater AUC of M2 (148 against 27·1 μg min mL−1) after iv administration of DA-125. The mean plasma concentrations of M3, being the lowest among M1–M4, were detected only up to 15 min after iv administration of both DA-125 and ME2303 to mice, and 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 after iv administration of DA-125 than ME2303, resulting in a considerably greater AUC of M4 (197 against 61·9 μg min mL−1) after iv administration of DA-125. Similar results on M1 and M2 were also obtained from rats: the mean plasma concentrations of both M1 and M2 were significantly higher after iv administration of DA-125, 10 mg kg−1, than after ME2303. The plasma concentrations of M1, M2, and M4, and hence their 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 μg mL−1, were 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 were 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 administration 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 38·8 min, and the concentrations of M3 were negligible. After iv administration 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, reaching their peak at 5 min, decayed more slowly and were higher than those 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 half-life of 43·9 min and neither M2 nor M3 were detected in plasma. The following disposition mechanisms for M1, M2, M3, and M4 after iv administration 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 administration 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 administration of DA-125 could be due to the fast and almost complete formation 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 continuously formed from M3 and the formation of M4 from M2 was negligible; and (iv) reversible metabolism among M1–M4 did not take place. The following 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 the greater biliary excretion of unchanged ME2303 (approximately 30% of iv dose) than unchanged DA-125 and (ii) the lower plasma concentrations of M2 and M4 after iv administration of ME2303 than after DA-125 could be due to lower plasma concentrations of M1 and hence less formation of both M2 and M4 from M1. Liver showed the highest metabolic activity for M1 and a considerable amount of M1 was also metabolized in the kidney after 30 min incubation of 50 μg of DA-125 in 9000 g supernatant fraction of rat tissue homogenates. The mean amount of M1 remaining 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 the heart, lung, large intestine, and kidney at 15 min after iv administration of DA-125, 25 mg kg−1, to mice than after ME2303. M1, the active antineoplastic moiety of DA-125, had higher affinity for the lung after iv administration of DA-125 to mice than after ME2303, indicating that lung tumours could be subjected to a greater exposure to M1 after 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 μg). However, reversed results were obtained for M2 (267 against 467 μg). M3 and M4 were under the detection limit in the bile sample after iv administration of either DA-125 or ME2303.
Databáze: OpenAIRE
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