Carbaryl was well absorbed from the small intestine of rats. In the cytosol fraction of intestinal mucosa, it was bound to a smallmolecular component (M.W.2, 200 daltons). In serum, carbaryl was bound mainly to albumin and partly to globulins. Dieldrin was slowly absorbed from small intestine. The peak of dieldrin concentration in blood was observed 2.5 hr after the administration. Binding of dieldrin to mucosal protein in cytosol was not detectable. In serum, dieldrin was bound to lipoproteins, globulins and partly to albumin. Absorption of paraquat from the small intestine was more rapid than that of dieldrin in situ study. However, in vivo study, the absorption of paraquat was the lowest among these three chemicals. In the cytosol fraction of intestinal mucosa, paraquat was bound to a small-molecular component (M.W.3, 100 daltons). In serum, it was present in unbound fraction. In the comparative studies with protein diets, absorption of paraquat from small intestine in situ was higher in low protein diet rats than that in high protein diet rats. However, difference in absorption in vitro and in histopathological study was not noted between low protein diet rats and high protein diet rats.
In rats exposed to styrene for 4 hours, the rate constant of elimination and biological half life of styrene were 0.11 and about 6 hours for adipose tissue, and 0.3 to 0.4 and about 2 hours for the other tissues, respectively. The relative ratio of apparent distribution of styrene decreased in the order adipose tissue > > liver > brain > kidney > blood ≑spleen > muscle. Almost the same results were obtained in the experiment by intraperitoneal injection of styrene. Repeated 4-hour exposures at about 700 ppm daily for five days caused the results similar to those in a single exposure. A trend of increase in concentration of styrene was observed in adipose tissue by 5 successive intraperitoneal injections every 6 hours at a dose of 350 mg/kg.
In this study, an effect of single administration of organic thio-compounds on the combined use with uridine diphosphate glucuronic acid was investigated. In the single administration of organic thio-compounds to Wistar strain rats, the synthesis of glucuronide was slightly accelerated by glutathione or methionine, but it was not so much as in the single administration of UDPGA. The glucuronyltransferase activity was accelerated, when either taurine or methionine was administered in combination with UDPGA. None of these organic thio-compounds used in this study showed more significant inhibitory action of β-glucuronidase activity than UDPGA in the single administration. It was perceived, however that the inhibitory action of β-glucuronidase activity was much accelerated, when UDPGA was administered in combination either with taurine or methionine. In the administration of organic thio-compounds to Gunn strain rats, cysteine was detected to be the compound which accelerated the synthesis of glucuronide. It was also noted that no organic thio-compounds used in this study affected as influence on β-glucuronidase activity.
An approximately 50-fold increase in serum β-glucuronidase activity appeared 2 hours after the administration of such organophosphate insecticides as dichlorvs, diazinon and disulfoton and of a carbamate insecticide, carbaryl. The activities of other acid hydrolases in the serum such as ribonuclease, acid phosphatase, hyaluronidase and N-acetylglucosaminidase did not change significantly after the insecticide treatment. The response was related to the dose level and was evident after a single intraperitoneal dose of diazinon as low as 1.6 mg/kg. This appearence of an increase in β-glucuronidase was retarded by pretreatment with SKF 525A, an inhibitor of drug metabolizing enzyme. When β-glucuronidase was elevated by a large dose of diazinon, full response to a second dose of diazinon did not occur until approximately one month after administration of the first dose.
Chronic toxicity and recovery tests of labetalol hydrochloride, α-and β-adrenoceptor blocking agent, were carried out using male and female Wistar strain rats. The drug was orally administered at 50, 100 or 200 mg/kg/day for 9 months. In all the drug-treated groups, increase in salivation was observed from immediately after to 15 minutes after dosing through treatment period. Suppression of body weight gain was observed in male rats in the 200mg/kg/day group. Food comsumption tended to be higher in all the drug-treated groups than in the control group. Similar trend was seen also in water comsumption, and increase in urine volume was noted ih the groups treated with 100 and 200mg/kg/day. In the serum biochemical examination, dose-dependent elevation in potassium level was noted in all drug-treated groups, but the valued were within the range of physiological variation. In the 100 and 200 mg/kg/day groups, an increase was observed in the absolute heart weight and in its relative weight against body weight. Major abnormalities found in histopathological findings were ; swelling of parenchymatous cells in liver and kidney, swelling of fibers and swelling or proliferation of interstitial cells in cardiac and skeletal muscles, and congestion in spleen. No notable abnormality was found in any examination item in the recovery test. From these results, it was suggested that maximum non-toxic dose of, labetalol hydrochloride was about 50 mg/kg/day in male and female rats.
Mequitazine is a new phenothiazine derivative with potent antihistaminic activity developed by Pharmuka, Co. Ltd., in France. Although the action of this drug on central nervous system is reported to be very weak in the dose range used as antihistaminics, the CNS action cannot be neglected when the huge amount is applied. In order to predict the safety use of this drug in clinical therapy the ability to develop barbital-type physical dependence was investigated. In conclusion, a single dose suppression test and substitution test in barbital dependent mice, and also the primary dependence liability test after repeated administration of the drug in rats revealed that Mequitazine has no physical dependence liability even in the toxic dose.