The effect of pretreatment with antibiotics on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms was investigated. Latamoxef sodium (LMOX, 25 mg/kg/d, intravenously) and cephalexin (CEX, 16.7 mg/kg/d, orally) were administered for 1 or 3 d. The blood concentration of salicyluric acid and salicylic acid following oral, intracecal and rectal administration of salicyluric acid was determined. By the pretreatment with LMOX for 1 or 3 d, the blood concentration of salicylic acid following oral administration of salicyluric acid was slightly decreased. In rabbits pretreated with CEX for 3 d, the blood concentration of salicylic acid was detected at low concentration. By the pretreatment with LMOX and CEX, however, the decrease in the blood concentration of salicylic acid following rectal administration of salicyluric acid was not observed. Although the examination of population of intestinal microorganisms induced by the pretreatment with antibiotics was not performed, the metabolic activity of intestinal microorganisms may be changed.

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Effect of pyrrolidone derivatives on lipid membrane and protein conformation has been assessed to obtain fundamental information about a mechanism of transdermal penetration enhancer. Their effects on a release of 6-carboxyfluorescein from liposome were examined. The lipophilic derivatives enhanced a release of dye and the enhancing effect showed a concentration dependency. Especially 1-lauryl-2-pyrrolidone showed the highest effect at the lowest concentration. The pyrrolidone derivatives also increased a hemolysis of rat erythrocytes. The derivatives slightly liberated SH group of keratin but did not change the electrophoresis pattern of keratin. 1-Methyl-2-pyrrolidone increased and retained a hydration of rat skin although 1-hexyl- and 1-lauryl-2-pyrrolidone showed no increase. These results suggest that the high enhancing effect of II, III and IX, as shown in the previous study, may be predominantly due to their interaction with skin lipid and their penetration behavior into the lipid.

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The pharmacokinetics and first-pass effect of bromhexine (BH) were studied in rats. Upon i.v. administration of 0.3 and 1 mg/kg of BH hydrochloride to normal rats, the plasma concentrations followed a biexponential curve, with slower terminal elimination (t_1/2β=8.9-11 h). In bile duct cannulated rats, the plasma concentration-time profile was similar to that of normal rats and the bile excreted within 30 h contained only 1.5±1.2% of the dose as intact and conjugated BH. These results suggest that a slower terminal elimination of BH after i.v. injection is due to a relatively small plasma clearance and large distribution volume rather than the enterohepatic recycling of the drug. Renal clearance of BH was negligible since urinary excretion of intact BH for 24 h after i.v. injection did not exceed 1% of the dose. After oral administration of BH, the systemic availability ranged only 1.8-3.9% based on i.v. and oral data, showing the poor bioavailability of oral BH. The first-pass effect of BH was measured by comparing the area under plasma concentration-time curve (AUC) after i.v., oral or hepatic portal (h.p.v.) administration of the drug. The AUC following h.p.v. dosing was only one-tenth of that obtained following i.v. administration and the AUC after oral dose was a quarter of that after h.p.v. administration. The hepatic extraction ratio was estimated to be 0.92. A low bioavailability after oral BH was explained by both hepatic and intestinal first-pass clearance, but mainly due to hepatic extraction.

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2-Chloromercurio-4-nitrophenol reacts reversibly with thiouridine, this reaction was applied to a chemical modification of E. coli transfer ribonucleic acid

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By the organomercurial column : chromagel or Sephadex coupled to p-aminophenylmercury chloride, 4- and 2-thiouridine were selectively separated from the mixtures with major nucleotides. Oligonucleotides containing 4-thiouridilic acid were also separated from the ribonuclease-T₁ digests of unfractionated transfer ribonucleic acid of E. coli.

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Formation of gastric lesions induced by orally administered aspirin (100 mg/kg) was examined in 4 to 86 week-old Sprague-Dawley male rats. Gastric mucosal prostaglandin I₂ (PGI₂) level and gastric secretion in basal state were also examined in these rats. Gastric mucosal PGI₂ level was measured by bioassay and gastric secretion was collected by the pyloric ligation method for 4 h. Gastric lesions reached the maximum value in 7 week-old, and lowest in 60 week-old. Acid output also reached the maximum value in 7 week-old. As for PGI₂ level, it showed the maximum value in 20 week-old, and moderately decreased thereafter. In 86 week-old, PGI₂ level was further lowered to about 35% of 20 week-old rats. A linear positive correlation was noted between formation of aspirin-induced gastric lesion and acid secretion. From these results, it was concluded that formation of gastric lesions by aspirin was closely related to acidity of the gastric secretion. It was also suggested that in aged rats, aspirin-induced gastric lesions may at least partly be associated with the reduced PGI₂ level.

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Metabolism in vivo of 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB) and toxicological assessment of the metabolite were investigated using male Wistar rats. Only one metabolite was isolated from the feces of rats administered 3, 4, 5, 3', 4'-PenCB. By gas chromatography-mass spectrometry, the methylated metabolite was identified with the synthesized authentic sample, 4'-methoxy-3, 4, 5, 3', 5'-PenCB. This indicated that the metabolite was 4'-hydroxy-3, 4, 5, 3', 5'-PenCB, which was produced via a 4', 5'-epoxide formation and subsequent NIH-shift of the 4'-chlorine to the 5'-position. Administration of the metabolite at either single i.p. dose of 3 or 10 mg/kg to rats did not cause any toxic and biological effects such as body weight loss, atrophy of thymus and spleen, liver hypertrophy, increase of liver lipids, or 3-methylcholanthrene-type induction of liver enzymes. These changes were observed in rats administered with 3, 4, 5, 3', 4'-PenCB at a single dose of 3 mg/kg. In addition, a trace amount of 4'-hydroxy-3, 4, 5, 3', 5'-PenCB could be detected in rat liver 5 d after treatment with 3, 4, 5, 3', 4'-PenCB or 4'-hydroxy-3, 4, 5, 3', 5'-PenCB. The amount of this metabolite excreted in feces during 5 d after treatment with 3, 4, 5, 3', 4'-PenCB accounted for only 1.3% of dose. In 4'-hydroxy-3, 4, 5, 3', 5'-PenCB-treated rats, about 60% of dose was excreted as unchanged in feces for 5 d. These results suggest that this metabolite is a detoxified product and has no longer the high affinity for the liver, being excreted rapidly into the feces.

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The effect of treatment of rats with ginsenosides (extracted from Panax ginseng) on transport of p-aminohippurate (PAH) in renal cortical slices was studied for an in vitro reflection of PAH secretion in the proximal tubules in the kidney. The treatment of rats with ginsenosides stimulated PAH accumulation in the slices and tended to prevent the decrease in PAH accumulation in incubated slices from the rats with acute renal failure caused by cisplatin or ischemia followed by reperfusion. Ginsenoside treatment affected other biochemical responses in renal cortical slices, with a decrease in adenosine triphosphate level and an increase in potassium level. The latter may lead to the stimulation of PAH transport in the slices, but additional information on the cellular action of ginsenosides is needed for this conclusion. It may be that the stimulatory effect of ginsenosides on PAH accumulation in the slices counterbalances the decrease in PAH accumulation in the slices from rats with acute renal failure.

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Effects of intraperitoneal (i.p.) administration of SSG, a (1→3)-β-D-glucan obtained from the culture filtrate of Sclerotinia sclerotiorum IFO 9395, on hematopoietic responses of mice were investigated. Numbers of spleen and peripheral leukocytes increased 7 d after administration of SSG (250μg/mouse). The percentages of polymorphonuclear leukocytes (PMN) in both spleen and peripheral blood increased markedly. The numbers of macrophage progenitor cells also increased in both spleens and femurs of the mice administered SSG. Furthermore, levels of colony-stimulating activity (CSA) in sera were elevated, and two peaks were observed (at 6 h and on day 7 after administration). Elevated CSAs were also observed in the cultures of peritoneal cells taken from mice 3 or 6 h after administration of SSG. These results may suggest that i.p. administration of SSG into mice enhanced the production of colony-stimulating factors (CSFs), and then increased the numbers of both spleen and peripheral blood leukocytes.

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