Sodium N-benzyl-D-glucamine dithiocarbamate (BGD), sodium N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD), sodium N-p-carboxybenzyl-D-glucamine dithiocarbamate (CBGD), and sodium N-p-methoxybenzyl-D-glucamine dithiocarbamate (MeOBGD) were evaluated for their efficacy in the distribution and excretion of cadmium in rats exposed to cadmium. Rats were injected intraperitoneally with ¹⁰⁹CdCl₂ (1 mg Cd/kg and 74 kBq of ¹⁰⁹Cd/one animal) and 30 min or 24 h later, they were injected with chelating agents all significantly enhanced the biliary excretion of cadmium. At 24 h after cadmium injection, BGD and MeOBGD were the most effective on the biliary excretion of the metal. These chelating agents were effective in mobilizing cadmium from the liver at 30 min after cadmium treatment. At 24 h after cadmium treatment, BGD and MeOBGD significantly depressed cadmium content in the liver. In another experiment, rats were injected intraperitoneally with ¹⁰⁹CdCl₂ and 3 d later, they were injected with BGD, HBGD, or MeOBGD every other day for 2 weeks. The fecal excretion of cadmium was significantly increased by these chelating agents and MeOBGD was the most effective. The hepatic and renal cadmium contents were significantly decreased after BGD, HBGD or MeOBGD injection. The injection of MeOBGD to rats pretreated with cadmium was more effective than that of BGD, HBGD, or CBGD in removing cadmium from the liver. HBGD injection was more effective in decreasing the cadmium content in the kidney. The treatment with these chelating agents did not cause the redistribution of cadmium to brain, testes, and heart.

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Intestinal absorption, biliary excretion and metabolism of a calcium gallstone dissolving agent, [11, 12-³H] ursodeoxycholyl-N-carboxymethylglycine (UDC-CMG) and its monoethyl, diethyl and dipivaloyloxyethyl esters (UDC-CMG-Et, UDC-CMG-Et₂ and UDC-CMG-PV₂) were studied in bile duct cannulated rats. Biliary recovery of [³H]-labeled UDC-CMG, UDC-CMG-Et and UDC-CMG-Et₂ after intraduodenal administration were 65%, 80%, 98%, respectively. Radio-thin layer chromatography analysis of the bile revealed that UDC-CMG didn't undergo any biotransformation during administration and excretion. About 80% and 20% of radioactivity recovered in the bile was identified as UDC-CMG-Et and UDC-CMG, respectively, after intraduodenal administrations of [³H] UDC-CMG-Et₂ and [³H] UDC-CMG-Et. The administered intact UDC-CMG-Et₂ was not found in the bile. Intraduodenally administered [³H] UDC-CMG-PV₂ was rapidly recovered in the bile. The total recovery rate was 78% within a 24 h period. More than 80% of the radioactivity recovered in the bile was found as UDC-CMG. Lesser amounts of the monopivaloyloxyethyl ester of UDC-CMG were also found, but intact UDC-CMG-PV₂ was not detected in the bile as in the case of UDC-CMG-Et₂. Among the esters of UDC-CMG investigated in the present studies, only UDC-CMG-PV₂ was excreted in the bile mainly as the perhydrolyzed form, UDC-CMG. These results suggest the usefulness of UDC-CMG-PV₂ as the pro-drug in calcium gallstone dissolution therapy.

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Four commercial controlled-release tablets of d-chlorpheniramine maleate, which showed various drug release properties, were administered to beagle dogs, and the correlation between in vitro drug release and in vivo absorption was studied. The mean in vivo absorption amount-time profile for each product showed good accordance with the in vitro drug release profile until 2-3 h after administration. However, absorption of the drug in dogs terminated at about 3 h. This short absorption time may be due to a short intestinal residence time for these dosage forms in the dog. In the present study, the deconvolution method was proved to be useful for in vitro/in vivo comparison, which clarified the in vivo absorption of controlled-release dosage forms having various release profiles.

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In order to assess mechanisms for acquired resistance to 5-fluorouracil (5-FU) of P388 cells on a cellular basis, we compared sensitivities of P388 and its 5-FU-resistant subline (P388/5-FU) cells to 5-FU, 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd). P388/5-FU cells exhibited an approximately 10-fold resistance to 5-FU and 170-fold cross-resistance to FUrd but not to FdUrd when they were exposed to each agent for 5 h in vitro. 5-FU-induced growth inhibition was hardly reversed with thymidine, suggesting its ribonucleic acid (RNA)-directed effect. This was supported by the fact that similar amounts of 5-FU were incorporated into cellular RNA in P388 and P388/5-FU when these cells were incubated with equitoxic concentrations of 5-FU. Furthermore, incorporation of 5-FU and FUrd into cellular RNA in P388/5-FU cells were significantly lower than in P388 cells when cells were exposed to them at the same concentration. These results suggest a major action of 5-FU is directed toward RNA in these cells at least under the present experimental condition, and 5-FU resistance of this cell line is closely associated with reduced uridine kinase activity among various enzymatic changes previously observed.

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The permeability of fosfomycin (FOM), which is a low molecular weight and water-soluble antibiotic, across rat and rabbit jejunal membrane was investigated on a paracellular route and a transcellular route separated by voltage-clamp method. It was determined that FOM permeates through these two routes in both animals. Under a physiologically normal condition, the transmucosal electrical potential difference (about 2 mV), the contribution of the transcellular route to FOM membrane permeability was greater than that of the paracellular route. The transcellular permeability was significantly reduced in the presence of inorganic phosphate. The inhibitory effects of the inorganic phosphate coincided with our reports on FOM uptake by rat jejunal brush-border membrane vesicles in vitro and on FOM absorption by rat jejunal single-pass perfusion in situ.

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Oil violet in a fat emulsion was taken up into the parenchymal cells of rat liver in vitro. The uptake was greater at 37 °C than 25 °C or 4 °C, and it was increased by addition of postheparin plasma including lipoprotein lipase activity into the reaction medium. The uptake from the emulsion with smaller particles was greater than that from the emulsion with larger particles. The hepatic uptake of ¹⁴C-cholesteryl oleate in the emulsion by recirculating perfusion of the liver in situ was also increased by postheparin plasma in the perfusion medium. Its enhancing effect was found for distribution in the parenchymal cells but not in the Kupffer cells. The previous perfusion of Intralipos of the commercial fat emulsion reduced the hepatic uptake of ¹⁴C-cholesteryl oleate in the emulsion. The emulsion particle sizes were reduced by postheparin plasma both in vitro and in situ. Consequently, it was suggested that a lipid-soluble compound entrapped in the fat emulsion is taken up into the parenchymal cells by receptor-mediated process via the reduced particle sizes emulsion (remnant), which is a mechanism similar to the dietary fat metabolism.

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It was found that the fluorescence of 9, 10-dioxa-syn-3, 4, 6, 7-tetramethylbimane (bimane) can be quenched in the presence of dimethylaminoazobenzensulfonyl (Dabsyl) group. New combination of bimane (fluorophor) and dabsyl group (quencher) was applied to the syntheses of intramolecularly quenched fluorogenic substrates for hydrolytic enzymes. Bimane peptides containing dabsyl group were prepared, and were shown to be useful fluorogenic substrates for the assay of endopeptidases such as chymotrypsin, collagenase and thermolysin

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