MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4- oxothiazolidin-2-ylidenemethyl] pyridinium chloride), a novel rhodacyanine dye in phase I/II clinical trials, may provide a new approach to cancer therapy based on the accumulation in the mitochondria of the cells of certain carcinomas, for example, those of the colon, breast and pancreas. To support the development of MKT-077 for clinical application as an intravenous (i.v.) therapy, we investigated the metabolic fate of [14C]MKT-077 in BDF1 mice as well as the distribution of MKT-077 in experimental LS174T tumor-bearing mice using a high-performance liquid chromatography (HPLC) method. The plasma levels of 14C after i.v. administration of [14C]MKT-077 declined in a triphasic manner. In the first distribution phase, the levels of 14C decreased with a T1/2 of approximately 5 min. In the second and terminal phase, the T1/2 of 14C was 2.8-4.6 h and 16.2 h, respectively. Cmax (1 min after injection) increased from 0.3 to 1.5 microg/ml linearly, but less than proportionately between the doses. The AUC(0-infinity) at 0.3, 1 and 3 mg/kg were 0.030 +/- 0.002, 0.60 +/- 0.12 and 1.73 +/- 0.25 microg x h/ml, respectively. Plasma clearance was approximately 1.8 l/h per kg (at doses of 1 and 3 mg/kg). The steady state volume of distribution (6.8 and 25.1 l/kg) indicated that MKT-077 distributed as a lipid-soluble molecule. The mean residence time (MRT) was 4.1 (at a dose of 1 mg/kg) and 14.1 h (at a dose of 3 mg/kg). In the first rapid phase (5 min after dosing), 14C radioactivity was detected in most of the tissues and organs, most strongly in the kidney cortex, and not in the central nervous system and testes. In the terminal phase (24 h after dosing), 14C contents increased in the intestinal tract, and in the kidney and liver were nearly to the background level. After i.v. bolus administration at a dose of 3 mg/kg of [14C]MKT-077, the predominant route of elimination of the radioactivity was via the feces, and recoveries of total radioactivity in urine and feces corresponded to 33.5% and 61.1%, respectively. More than 60% was recovered within 24 h and 95% within 1 week. MKT-077 was primarily excreted in unmetabolized form with five unidentified metabolites found in the urine and plasma. Intact MKT-077 was retained in the tumor tissue longer than in plasma and kidney in LS174T tumor-bearing mice receiving MKT-077 at an i.v. therapeutic dose (10 mg/kg). This accumulation decreased very slowly, suggesting that the high membrane potentials of tumor cell mitochondria may help retain the drug in tumors.

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The aim of this study was to elucidate whether or not quantitative analysis of autoradiographs could be obtained with a [14C]-labelled compound by the use of new type radiosensor, so called 'imaging plate' (IP). Since X-ray films were first used as a radiosensor for macroautoradiography by Ullberg (1), many kinds of X-ray films have been used but the other sensors have never been used. Our results indicated that there was an excellent relation between relative intensity (PSL-BG) and radioactivity on a given area which was completely linear. The linearity was observed in a relatively wide range between 10(1)-10(5) dpm orders of radioactivity. About 100 times greater sensitivity of the IP than any X-ray film was demonstrated by the use of not only [14C]-radioactive standard sources but also by experimentally provided [14C)-radioactive spots developed on a TLC plate and macroautoradiographs (MARG). In order to obtain reliable quantitative data from a MARG image, it was required that a thin specimen section be kept at a constant level of thickness under freezing condition through out the exposure time. Results also showed that the linear relation of relative intensity versus radioactivity of the specimens had a very wide range from 10(1)-10(5) dpm/mg of exposure within 7 days. Furthermore, the relation of relative intensity versus relative exposure (radioactivity x exposure time) was linear within the latitude of relative intensity form 10(1)-10(5) (PSL-BG). Finally, a combination of the IP and BAS2000, computerized image display system, was well equipped to completely erase a background memory before use.

Evidence is presented to elucidate whether or not quantitative analysis of autoradiographs can be obtained with a 14C-labelled compound by the use of a new type of radiosensor called Imaging plate (IP). Our results showed that a linear relationship between relative intensity of PSL-BG and radioactivity of a given area was obtained. The linearity was maintained in a relatively wide range from 10(1) to 10(5) dpm of radioactivity. About 100 times higher sensitivity of the IP than any commercially available X-ray film was demonstrated for not only 14C-radioactive standard sources but also experimentally obtained 14C-radioactive spots developed on a TLC plate. Results also showed a linear relationship between relative intensity and radioactivity of the specimens in a very wide range from 10(1) to 10(5) dpm/mg after exposure for 7d. Furthermore, the relationship between PSL-BG and relative exposure (radioactivity x exposure time) was linear when PSL-BG was from 10(1) to 10(5). In addition to the above properties, a combination of IP and BAS2000, a computerized image display system, was able to completely erase the background prior to use.

The results of this study show clearly that most of the administered DW-166HC remained at the administration site. It is concluded that the chitosan complex may be used to retain 166Ho within a limited area in cancer of the prostate.