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Pharmacokinetics and antitumour activity of a new anthracycline, DA‐125, after intravenous administration to subcutaneously implanted Lewis‐lung‐carcinoma‐bearing mice
Author(s) -
Lee Sang D.,
Park Jeong B.,
Lee Woo I.,
Shim Hyun J.,
Lee Eung D.,
Lee Jong J.,
Kim Won B.,
Yang Junnick,
Kim Chong K.,
Lee Myung G.
Publication year - 1995
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510160607
Subject(s) - pharmacokinetics , lewis lung carcinoma , metabolite , urine , cmax , lung , pharmacology , ratón , chemistry , medicine , excretion , endocrinology , cancer , metastasis
Abstract The pharmacokinetics and tissue distribution of M1–M4 were compared after intravenous (IV) administration of DA‐125, 25 mg kg −1 , to BDF 1 mice ( n = 5 at each sampling time) and subcutaneously implanted Lewis‐lung‐carcinoma‐bearing BDF 1 mice ( n = 10 at each sampling time). The mean plasma concentrations of M1–M4 were not significantly different between the two groups of mice, and hence similar pharmacokinetic parameters for M1–M4 were obtained. The amount of M1 in the lung was significantly greater in the tumour‐bearing mice than in the control mice, resulting in a greater AUA, in the tumour‐bearing mice (18 600 against 8940 μg min g −1 ), and vice versa in the liver (962 against 3840 μg min g −1 ). However, the corresponding values for other tissues were comparable between the control and tumour‐bearing mice. The amount of M1 was greatest in the lung for up to 2 h in the tumour‐bearing mice. M2 was the predominant metabolite among M1–M4 excreted in 24 h urine by both groups of mice; 8.36 and 10.7% of the IV dose were excreted in 24 h urine as M2–expressed in terms of DA‐125—by the control and tumour‐bearing mice, respectively. The amount of M1 in the tumour mass reached a mean C max of 3.75 μg g −1 immediately after IV administration of DA‐125 to the tumour‐bearing mice, then declined very slowly to an amount that remained almost constant for up to 24 h. This suggested that M1 has high affinity for the subcutaneously implanted Lewis lung carcinoma. The antitumour activity, such as the increase in life span (ILS) and tumour growth inhibition (TGI) of DA‐125, 6–48 mg kg −1 , and adriamycin (ADM), 3–18 mg kg −1 , were also compared in subcutaneously implanted Lewis‐lung‐carcinoma‐bearing BDF 1 mice after four weekly IV administrations of the drugs on days 1, 8, 15, and 22 following tumour implantation. More than three out of six mice survived as tumour‐free for longer than 70 d at a DA‐125 dose range of 6–24 mg kg −1 , but there were no tumour‐free mice at any dose of ADM. Assuming ILS values higher than 30% to be effective, DA‐125 doses ranging from 6 to 24 mg kg −1 were effective in increasing the life span, which ADM dose only within the dose range of 6–12 mg kg −1 .