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The pharmacokinetics and tissue distribution of M1-M4 were compared after intravenous (i.v.) administration of DA-125, 25 mg kg-1, to BDF1 mice (n = 5 at each sampling time) and subcutaneously implanted Lewis-lung-carcinoma-bearing BDF1 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 AUAt in the tumour-bearing mice (18,600 against 8940 micrograms min g-1), and vice versa in the liver (962 against 3840 micrograms 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 i.v. 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 Cmax of 3.75 micrograms g-1 immediately after i.v. 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 BDF1 mice after four weekly i.v. administration 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 does only within the dose range of 6-12 mg kg-1.
The pharmacokinetics and tissue distribution of M1-M4 were compared after intravenous (i.v.) administration of DA-125, 25 mg kg-1, to BDF1 mice (n = 5 at each sampling time) and subcutaneously implanted Lewis-lung-carcinoma-bearing BDF1 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 AUAt in the tumour-bearing mice (18,600 against 8940 micrograms min g-1), and vice versa in the liver (962 against 3840 micrograms 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 i.v. 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 Cmax of 3.75 micrograms g-1 immediately after i.v. 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 BDF1 mice after four weekly i.v. administration 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 does only within the dose range of 6-12 mg kg-1.
The rats with protein-calorie malnutrition (PCM, 5% casein diet for a period of 4-week) were reported to exhibit 60 and 80% suppression in the hepatic microsomal cytochrome P450 (CYP) 1A2 and CYP2C11 levels, respectively, and 40-50% decreases in CYP2E1 and CYP3A1/2 levels compared to control (23% casein diet for a period of 4-week) based on Western blot analysis. In addition, Northern blot analysis showed that CYP1A2, CYP2E1, CYP2C11, and CYP3A1/2 mRNAs decreased in the state of PCM as well. Hence, pharmacokinetic changes of the drugs in rats with PCM [especially the area under the plasma concentration-time curve from time zero to time infinity (AUC) changes of metabolite(s)] reported from literatures were tried to explain in terms of CYP isozyme changes in the rats. Otherwise, the time-averaged nonrenal clearance (CL NR) of parent drug was compared. Pharmacokinetic changes of the drugs in other types of malnutritional state, such as kwashiorkor and marasmus, in both human and animal models were also compared. The drugs reviewed are as follows: diuretics, antibiotics, anticancer agents, antiepileptics, antiarrythmics, analgesics, xanthines, antimalarials, and miscellaneous.
To predict the clinical usefulness of DA-125, a newly developed doxorubicin analog, we compared its antitumor activity against 20 different human cancer cell lines with that of doxorubicin using the MTT in vitro chemosensitivity test. We also measured and compared the cellular uptake of this drug and doxorubicin in two cancer cell lines and their doxorubicin-resistant sublines. In the MTT test, DA-125 showed lower IC50 values than doxorubicin for 14 of 20 cell lines. DA-125 was more potent than doxorubicin for hepatocellular cancer cells with high mdr 1 expression. Among cancer cells from the stomach and colon, DA-125 was more potent than doxorubicin in 12 of 14 cell lines. We also investigated the cross-resistance of this drug with doxorubicin using four doxorubicin-resistant cancer cell sublines. Except in one cell line, there was very low cross-resistance. Cellular drug-uptake experiments were performed for two gastric cancer cell lines and their doxorubicin-resistant sublines. In this experiment, DA-125 was found to be very rapidly and completely converted to its active metabolite, M1, in the culture media. After this conversion, M1 was incorporated into these cancer cells more rapidly and reached higher intracellular concentrations than doxorubicin, suggesting that DA-125 (as M1) could achieve earlier and higher levels of intracellular accumulation than doxorubicin in its target tissues from the bloodstream. As a possible alternative antineoplastic agent to doxorubicin, DA-125 awaits further evaluation for its antitumor activity and toxicity.
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