Hyun J. Shim

Pharmacokinetics of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM or FT-ADM to rats. A new adriamycin analog containing fluorine

The pharmacokinetics of DA-125 or its active metabolite, M1 (FT-ADM), an adriamycin analog containing fluorine were compared after intravenous (i.v.) administration of DA-125 or M1 in rats. DA-125, 20 mg kg−1 was dissolved in 1 mM lactic acid/0.9% NaCl solution (treatment I) or 100% dimethylsulfoxide (DMSO, treatment II), and M1, 20 mgkg was dissolved in 100% DMSO (treatment III) due to its poor water solubility. The plasma concentrations of DA-125 and M1, and the pharmacokinetic parameters of DA-125, such as terminal half-life (t12, 1.64 vs 2.07 min), mean residence time (MRT, 1.52 vs 2.60 min), total body clearance (CL, 165 vs 186 ml min−1 kg−1) and apparent volume of distribution at steady state (Vdss, 254 vs 411 ml kg−1), and of M1 (based on plasma data up to 1 h), such as (t12 (30.2 vs 38.7 min), MRT (19.1 vs 31.6 min), CL (187 vs 189 ml min−1 kg−1) and Vdss(2670vs 5700 ml kg−1were similar between treatments I and II, indicating that the effect of 100% DMSO on the pharmacokinetics of DA-125 or M1 seemed to be negligible, if any. The plasma concentrations of M1, and the pharmacokinetic parameters of M1 (based on plasma data up to 8 h when the dose of M1, 20 mg kg−1 was normalized to the dose of DA-125, 20 mg kg−1), such as (t12 (255 vs 221 min), MRT (269 vs 235 min), CL (103 vs 112 ml min−1 kg−1) and Vdss (28 500 vs 26300 ml kg−1) were also similar between treatments II and III. The above results indicate that DA-125 is rapidly hydrolyzed to M1 after i.v. administration of DA-125. Therefore, the estimation of the pharmacokinetic parameters of M1 after i.v. administra- tion of DA-125 appeared not to cause any differences, if any when compared with the values after i.v. dose of M1. The rapid hydrolysis of DA-125 to M1 was demonstrated during an in vitro study; the (t12 values of hydrolysis of DA-125 were 1.97, 1.72, 0.54 and 0.54 min in the plasma from mouse, rat, dog and human, respectively, when the plasma containing DA-125 was incubated in a shaking water bath kept at 37°C and at a rate of 300 rpm.

North Ecliptic Pole Wide Field Survey of AKARI: Survey Strategy and Data Characteristics

We present the survey strategy and the data characteristics of the North Ecliptic Pole (NEP) Wide Survey of AKARI. The survey was carried out for about one year starting from 2006 May with 9 passbands from 2.5 to 24� m and the areal coverage of about 5.8 degree 2 centered on NEP. The survey depth reaches to 21.8 AB magnitude near infrared (NIR) bands, and � 18.6 AB magnitude at the mid infrared (MIR) bands such as 15 and 18 � m. The total number of sources detected in this survey is about 104000, with more sources in NIR than in the MIR. We have cross matched infrared sources with optically identified sources in CFHT imaging survey which covered about 2d egree 2 within NEP-Wide survey region in order to characterize the nature of infrared sources. The majority of the MIR sources at 15 and 18 � m bands are found to be star forming disk galaxies, with smaller fraction of early type galaxies and AGNs. We found that a large fraction (60%–80%) of bright sources in 9 and 11 � m is stars while stellar fraction decreases toward fainter sources. We present the histograms of the sources at MIR bands at 9, 11, 15, and 18 � m. The number of sources per magnitude thus varies as m 0:6 for longer wavelength sources while shorter wavelength sources show steeper variation with m ,w herem is the AB magnitude.

Pharmacokinetics, tissue distribution and biliary excretion of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM to dogs. A new adriamycin analog containing fluorine

Abstract The pharmacokinetic parameters, tissue distribution and biliary excretion of M1-M4 were estimated after intravenous (i.v.) administration of DA-125, 2.5 mg per kg to beagle dogs. The mean values of the terminal half-life, mean residence time, total body clearance and apparent volume of distribution at steady state of M1 were 266 min, 170 min, 61.3 ml min −1 kg −1 and 9500 ml kg −1 , respectively (four male and four female dogs). M1 was highly concentrated in lung (five male and five female dogs), and this probably means that lung tumors are subjected to greater exposure to M1, an active metabolite of DA-125. The 8 h biliary excretion of M2 was significantly greater than that of M1, 53.6 vs 6860 μg (three male and two female dogs). The amount of glucuronide and/or sulfate conjugates of M1-M4 in the bile sample was negligible.

Pharmacokinetics of intravenous and oral DA-8159, a new erectogenic, in rats with protein-calorie malnutrition.

Influence of dietary protein deficiency on the pharmacokinetics of DA‐8159 and one of its metabolites, DA‐8164, was investigated after intravenous and oral administration of DA‐8159 at a dose of 30 mg kg−1 to male Sprague‐Dawley rats allowed free access to a 23% (control) or 5% (protein‐calorie malnutrition, PCM) casein diet for 4 weeks. The total area under the plasma concentration‐time curve from time zero to time infinity (AUC) values of DA‐8164 were significantly smaller after both intravenous (87.0 vs 162 μg min mL−1) and oral (144 vs 319 μg min mL−1) administration of DA‐8159 to PCM rats. This could be due to the decrease in CYP3A1/2 (50–60%) in the rats because DA‐8164 was mainly formed via CYP3A1/ 2 in rats. This could be supported by significantly slower in‐vitro CLint (2.04 ± 0.646 vs 3.15 ± 0.693 μL min−1 (mg protein)−1) for the formation of DA‐8164 in hepatic microsomal fraction of PCM rats. After intravenous administration of DA‐8159, the AUC values of DA‐8159 were not significantly different between the two groups of rats although the AUC of DA‐8164 was significantly smaller in PCM rats, and this may be due to the minor metabolic pathway of DA‐8164 in rats. However, after oral administration of DA‐8159, the AUC of DA‐8159 was significantly greater in PCM rats (194 vs 122 μg min mL−1). This was not due to enhanced absorption of DA‐8159 from the gastrointestinal tract in the rats but may be due to a decreased intestinal first‐pass effect of DA‐8159 in the rat.

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

The pharmacokinetics of M1, M2, M3 and/or M4 were compared after intravenous (i.v.) 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 i.v. 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 micrograms min mL(-1)) and a considerably slower CL of M1 (69.3 against 136 mL min-1 kg(-1)) after i.v. 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 i.v. administration of DA-125. The mean plasma concentrations of M2 were detected up to 8 and 4 h after i.v. 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 micrograms min mL(-1)) after i.v. administration of DA-125. The mean plasma concentrations of M3, being the lowest among M1-M4, were detected only up to 15 min after i.v. administration of both DA-125 and ME2303 to mice, and were comparable after i.v. administration of DA-125 and ME2303 to mice. The mean plasma concentrations of M4 were detected up to 8 h after i.v. administration of both DA-125 and ME2303 to mice, and were higher after i.v. administration of DA-125 than ME2303, resulting in a considerably greater AUC of M4 (197 against 61.9 micrograms min mL(-1)) after i.v. 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 i.v. 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 i.v. 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 micrograms mL(-1), were maintained from 30 min to 8-10 h after i.v. 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 i.v. 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 i.v. 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 i.v. administration of M3, 5 mg kg(-1), was comparable to that after i.v. 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 i.v. administration of either M2 or M3 to rats. After i.v. 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 i.v. 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 i.v. administration of DA-125 than those after i.v. 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 i.v. administration of DA-125 could be due to the fast and almost complete information 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 (i.v.) reversible me

Pharmacokinetics of a non‐narcotic analgesic, DA‐5018, in rats

The pharmacokinetics of a non‐narcotic analgesic, DA‐5018, were compared after single intravenous (IV), subcutaneous (SC), and oral administrations, and after multiple (seven consecutive days) SC administration to rats. After IV administration of DA‐5018, 1, 2, and 5 mg kg−1, the pharmacokinetic parameters of DA‐5018 were independent of the dose ranges studied. After oral administration of DA‐5018, absorption of the drug from gastrointestinal (GI) tract was fast, but the extent of absolute bioavailability (F) was low; the values were 23.2, 23.0, and 27.3% for 2, 5, and 10 mg kg−1, respectively. After single SC administration of DA‐5018, absorption of the drug from the injected site was fast and the extent of absorption was fairly good; the F values were 74.5 and 71.8% for 2 and 5 mg kg−1, respectively. The lower F values after oral administration of DA‐5018 to rats could be due to degradation of the drug in rat GI tract and/or considerable first‐pass effect. After IV, oral, and SC administration of DA‐5018, the drug had a strong affinity to the rat tissues studied as reflected in the greater‐than‐unity tissue to plasma ratio. After IV, oral, and SC administration of the drug, the biliary and urinary excretion of unchanged DA‐5018 were negligible. There was no significant difference in the pharmacokinetics or tissue distribution of DA‐5018 between single and multiple SC administration of the drug, 5 mg kg−1, to rats, indicating that there could be no tissue accumulation of the drug after multiple SC administration of the drug to rats.