{"title":"Biochemical studies on oral toxicity of ricin. IV. A fate of orally administered ricin in rats.","authors":"M Ishiguro, S Tanabe, Y Matori, R Sakakibara","doi":"10.1248/bpb1978.15.147","DOIUrl":"https://doi.org/10.1248/bpb1978.15.147","url":null,"abstract":"<p><p>After oral administration of ricin in rats, its distribution in the gastrointestinal tract, body fluids and principal organs was determined by an enzyme immunoassay, and the immunoreactive ricin detected was identified by gel filtration followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, protein blotting and the immunobinding method. When ricin D (10 mg/kg rat) was given orally to a rat, which dose is equivalent to 1/3 LD50, about 75% of the ricin was found in the stomach and small intestine within 2 h, and most of it was transferred to the large intestine after 24 h. It was also demonstrated by an in vitro toxicity test of immunoreactive ricin in the blood and lymph obtained from the intoxicated rats that a part of the ricin was absorbed from the small intestine into the tissues and organs via the circulatory systems (lymphatic and blood vessels) as the active ricin. The participation of the blood vessels was greater in the absorption of ricin from the gastrointestinal tract than that of the lymphatic system. Ricin, after absorption, was detected in liver and spleen and ricin found in the liver was predominantly in the form of intact ricin, although an undetectable amount of ricin in other organs cannot be eliminated. These results infer that a small fraction of orally-given ricin was transferred to the circulating system and was responsible for rat's death as in the case of i.p. administration.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 4","pages":"147-56"},"PeriodicalIF":0.0,"publicationDate":"1992-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12664165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Distribution of quinidine in rats with carbon tetrachloride-intoxicated hepatic disease.","authors":"N Sugihara, K Furuno, N Kita, T Murakami, N Yata","doi":"10.1248/bpb1978.15.167","DOIUrl":"https://doi.org/10.1248/bpb1978.15.167","url":null,"abstract":"<p><p>The disposition of quinidine was investigated in rats with experimental hepatic disease caused by an intraperitoneal injection of CCl4. The plasma disappearance of quinidine after a 12.5 mg/kg i.v. bolus injection was analyzed by a two-compartment open model in both control and CCl4-intoxicated rats. In the CCl4-intoxicated rats, plasma total body clearance (CLtot), elimination rate constant of the central compartment (kel) and the volume of distribution (Vdss) of quinidine were decreased by 73, 51 and 36%, respectively, compared to those in the control rats. At a steady state of quinidine plasma concentration of 1 micrograms/ml, tissue-to-plasma partition coefficient (Kp,vivo) of the drug in the lung, spleen, heart, kidney and liver in the CCl4-intoxicated rats were decreased ranging from 32 to 42% compared to those in the control rats. The plasma free fraction of quinidine in the intoxicated rats was decreased by 34% of that in the control rats. Neither tissue binding of quinidien in vitro, nor plasma pH was altered in the intoxicated rats. Thus, the decrease in Vdss and Kp,vivo for quinidine in the intoxicated rats seems likely to be due to an increase in plasma protein binding of the drug. Metabolic activity in the liver, the hepatic extraction ratio for quinidine, and the hepatic blood flow in the CCl4-intoxicated rats were decreased by 84, 57 and 47%, respectively, compared to those in the control rats. The decrease in CLtot and kel in the intoxicated rats is considered to be attributed to both the reduction of liver functions and the increase in the plasma protein binding of the drug.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 4","pages":"167-74"},"PeriodicalIF":0.0,"publicationDate":"1992-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12665710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S Kobayashi, T Naitoh, T Nakadate, I Kimura, M Kimura
{"title":"Suppression by high glucose concentration of insulin receptor up-regulation in diaphragm and flexor digitorum brevis muscles from diabetic KK-CAy and streptozotocin-diabetic mice.","authors":"S Kobayashi, T Naitoh, T Nakadate, I Kimura, M Kimura","doi":"10.1248/bpb1978.15.175","DOIUrl":"https://doi.org/10.1248/bpb1978.15.175","url":null,"abstract":"<p><p>The specific binding of insulin to diaphragm and flexor digitorum brevis (FDB) muscles isolated from diabetic KK-CAy and streptozotocin (STZ)-diabetic ddY mice was investigated under high glucose concentration in vitro. For high-affinity insulin receptor under 2.8 mM glucose, amounts of the receptor and values of dissociation constant (Kd) were greater in both diabetic muscles than in the corresponding normal control muscles, respectively. High glucose concentration up to 16.7 mM reduced both the up-regulation of the receptor and the decrease in the affinity by the diabetic state. These studies strongly suggest that high glucose level in the diabetic state in vivo may suppress the up-regulation of high-affinity insulin receptor in both models of diabetic mice.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 4","pages":"175-80"},"PeriodicalIF":0.0,"publicationDate":"1992-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12665713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K Miyake, H Fukuchi, T Kitaura, M Kimura, Y Kimura
{"title":"Pharmacokinetic analysis of amitriptyline and its demethylated metabolite in serum and brain of rats after acute and chronic oral administration of amitriptyline.","authors":"K Miyake, H Fukuchi, T Kitaura, M Kimura, Y Kimura","doi":"10.1248/bpb1978.15.157","DOIUrl":"https://doi.org/10.1248/bpb1978.15.157","url":null,"abstract":"<p><p>The compartmental model analysis by use of simultaneous curve fitting was carried out to ascertain the pharmacokinetic relationship between amitriptyline (AMT) and nortriptyline (NRT) in the serum and brain after acute or chronic oral administration of AMT. The estimated F value, a fraction of dose reached at systemic circulation, and the MD value, a fraction metabolized to NRT, were 0.044 and 0.020, respectively, after acute administration, indicating first-pass metabolism of AMT. The estimated parameters kin and kout, the transfer rate constants to and from the brain, showed no marked difference between AMT and NRT. These findings indicate equivalent ability of AMT and NRT to penetrate into the brain. The area under the concentration curve (AUC) values of AMT and NRT in the serum increased 1.4 and 8.2 times, respectively, with the increase of NRT being greater after chronic administration. The MD value was increased from 0.020 to 0.096, whereas the estimated F value showed no marked change. These results indicate the enhanced first-pass metabolism. The estimated transfer rate constants kin and kout of AMT were close to those of NRT. In addition, the transfer rate constants after chronic administration were similar to those after acute administration, indicating no marked change in penetration into the brain by multiple dosing.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 4","pages":"157-66"},"PeriodicalIF":0.0,"publicationDate":"1992-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12665708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effect of carrageenan-induced inflammation on the induction of hepatic microsomal enzymes by phenobarbital and benzo[a]pyrene in male rats.","authors":"M Ishikawa, K Sasaki, Y Takayanagi, K Sasaki","doi":"10.1248/bpb1978.15.139","DOIUrl":"https://doi.org/10.1248/bpb1978.15.139","url":null,"abstract":"<p><p>The inhibitory effect of carrageenan-induced inflammation was examined by utilizing rats treated with inducers of this drug metabolizing system. Animals were given sodium phenobarbital (PB, 80 mg/kg, i.p., 24 h prior to death), or benzo[a]pyrene (BP, 40 mg/kg, i.p., 24 h prior to death) as inducers. Some animals were also given carrageenan 24 h prior to death. Non-induced male rats exhibited significant decreases in hepatic 9000 x g supernatant (S-9) cytochrome P-450 and aminopyrine (AM) N-demethylase, benzphetamine (BenzP) N-demethylase and meperidine (MP) N-demethylase activity following carrageenan treatment. Carrageenan also depressed the induction of hepatic S-9 cytochrome P-450 content caused by PB treatment, and suppressed the induction of AM, BenzP, MP, arylhydrocarbon and 7-ethoxycoumarine metabolism by PB treatment. Cytochrome P-450 levels and related biotransformation activity which are elevated by BP treatment were not decreased by the injection of BP and carrageenan simultaneously to male rats. Non-induced, PB-treated and BP-treated female rats did not show inhibited carrageenan-induced reduction in hemoprotein content or inhibition of AM-N-demethylase, BenzP N-demethylase and aniline hydroxylase activities. These results demonstrate the selective nature of the inhibitory effects of carrageenan-induced inflammation upon drug metabolism in the rats.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 4","pages":"139-46"},"PeriodicalIF":0.0,"publicationDate":"1992-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12664164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A Kawaji, K Yamauchi, S Fujii, R Natsuki, E Takabatake, Y Yamaura
{"title":"Effects of mushroom toxins on glycogenolysis; comparison of toxicity of phalloidin, alpha-amanitin and DL-propargylglycine in isolated rat hepatocytes.","authors":"A Kawaji, K Yamauchi, S Fujii, R Natsuki, E Takabatake, Y Yamaura","doi":"10.1248/bpb1978.15.107","DOIUrl":"https://doi.org/10.1248/bpb1978.15.107","url":null,"abstract":"<p><p>The effects of phalloidin and alpha-amanitin as toxins of Amanita species and DL-propargylglycine identified from A. abrupta on the glycogenolysis in isolated rat hepatocytes were investigated. Phalloidin decreased glycogen content and activated phosphorylase a activity remarkably. alpha-Amanitin also decreased glycogen content significantly but activated phosphorylase a activity slightly. DL-Propargylglycine slightly affected glycogenolysis. Phalloidin, which most affected glycogenolysis among the three compounds mentioned above, elevated cytosolic Ca2+ concentration ([Ca2+]i) and 45Ca uptake into cells. Phalloidin depressed slightly 3H-inositol incorporation into phosphatidylinositol (PI) and remarkably phosphatidylinositol 4,5-bisphosphate (PIP2) but increased phosphoinositides breakdown. These results suggest that phalloidin alters phosphoinositides turnover and intracellular Ca2+ homeostasis, subsequently activates phosphorylase a, resulting in glycogenolysis in isolated rat hepatocytes.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 3","pages":"107-12"},"PeriodicalIF":0.0,"publicationDate":"1992-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12494747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Protective effects of benidipine hydrochloride (KW-3049), a calcium antagonist, against experimental arterial calcinosis and endothelial dysfunction in rats.","authors":"K Higo, A Karasawa, K Kubo","doi":"10.1248/bpb1978.15.113","DOIUrl":"https://doi.org/10.1248/bpb1978.15.113","url":null,"abstract":"<p><p>Protective effects of benidipine hydrochloride (KW-3049) against arterial calcinosis and its possible mechanisms of action have been investigated. Arterial calcinosis was induced in rats by combined administration of vitamin D2 (1050000 IU/kg, s.c.) and nicotine (12.5 mg/kg, p.o., b.i.d.) for 6 successive days. Calcium antagonists, benidipine or nifedipine, were given orally twice a day during the same period. The aortic calcium content in vitamin D2 and nicotine-treated (control) rats increased to about 25 times that in normal rats, accompanying an increase of serum calcium level. Benidipine (10 mg/kg, p.o., b.i.d.) reduced the aortic calcium content to about 18% of control rats without reducing the serum calcium level. Although the presence of aortic endothelial cells was observed under light microscopy in control rats, their surfaces were degenerated under scanning electron microscopy. Benidipine exerted a protective effect against these degenerative changes. Acetylcholine-induced endothelial dependent relaxation was attenuated in control rats, compared with that in normal rats. Benidipine significantly improved this attenuation of the relaxation. These results suggest that the anticalcinotic effect of benidipine is accompanied by its protective effect on endothelial cells.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 3","pages":"113-20"},"PeriodicalIF":0.0,"publicationDate":"1992-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12791648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Selective analysis of mutual displacement effects at the primary binding sites of phenoxymethylpenicillin and cephalothin bindings to human serum albumin.","authors":"T Terasaki, H Nouda, A Tsuji","doi":"10.1248/bpb1978.15.91","DOIUrl":"https://doi.org/10.1248/bpb1978.15.91","url":null,"abstract":"<p><p>In order to analyze the mutual displacement effects on the protein binding of beta-lactam antibiotics, binding experiments with the human serum albumin (HSA) were performed for cephalothin (CET) and phenoxymethylpenicillin (PCV) by using the centrifugal ultrafiltration method. The numbers of primary and secondary binding sites, n1 and n2, and the affinity constants for the primary and secondary binding sites, K1 and K2 were determined for CET to be 1.00 +/- 0.06 (mean +/- S.D.) and 4.54 +/- 0.12 and 2.59 x 10(3) +/- 0.10 x 10(3) (M-1) and 2.59 x 10(2) +/- 0.16 x 10(2) (M-1), respectively, and for PCV to be 0.94 +/- 0.10 and 5.41 +/- 0.40 and 3.52 x 10(3) +/- 0.25 x 10(3) (M-1) and 4.07 x 10(2) +/- 0.54 x 10(2) (M-1), respectively. Using the predicted optimum unbound concentration of PCV, i.e., 4.6 x 10(-4) M, the displacement effect of PCV to the binding of CET at the primary site has been demonstrated, while no significant effect was observed at the secondary binding site. Moreover, a competitive displacement effect of CET was also demonstrated for the binding of PCV to HSA at the primary binding site, suggesting that CET and PCV bound to HSA at the same primary binding site.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 3","pages":"91-7"},"PeriodicalIF":0.0,"publicationDate":"1992-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.91","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12791649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Highly sensitive enzyme-linked immunosorbent assay for marograstim (KW-2228), a mutant of human granulocyte colony-stimulating factor.","authors":"T Kuwabara, S Okumura, S Kobayashi, T Hirata","doi":"10.1248/bpb1978.15.121","DOIUrl":"https://doi.org/10.1248/bpb1978.15.121","url":null,"abstract":"<p><p>An enzyme-linked immunosorbent assay (ELISA) for marograstim (KW-2228) was established. This ELISA proved to be highly sensitive with the detection limit of 0.01 ng/ml (about 0.5 fmol/ml) of KW-2228 and the assay range between 0.01 and 2 ng/ml. When 0.02 to 2 ng/ml of KW-2228 added to human plasma was determined, the variation coefficiencies of intra-day and inter-day assays were 0.4 to 7.6% and 5.2 to 15.8%, respectively, with good recoveries. These results indicate that this ELISA will be applicable to pharmacokinetic studies on KW-2228. With respect to the specificity, recombinant human granulocyte colony-stimulating factor (rhG-CSF) produced in Escherichia coli as well as KW-2228 which does not have sugar chains in its structure showed slightly less immunoreactivity toward the antibody raised against KW-2228. The rhG-CSF produced in Chinese hamster ovary cells (CHO) having sugar chains showed the lower immunoreactivity. The antigenic domains of KW-2228 were evaluated using a number of variants of hG-CSF. The variants having different amino acids from KW-2228 in the 1st to 5th residue of the N-terminus showed almost equal immunoreactivities to KW-2228. The immunoreactivities of the variants lacking 7 to 18 amino acids of N-terminus were less than 50% of that of KW-2228. No immunoreactivity was observed for the variants deleted in the area of 70th to 130th amino acids from the N-terminus. In addition, the immunoreactivity of a variant lacking the 10 amino acids from the C-terminus was 20% of that of KW-2228.(ABSTRACT TRUNCATED AT 250 WORDS)</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 3","pages":"121-9"},"PeriodicalIF":0.0,"publicationDate":"1992-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12549904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E Gohda, T Matsunaga, H Kataoka, C Kasada, I Yamamoto
{"title":"Purification and characterization of a mouse hepatocyte growth-stimulating factor from the liver of carbon tetrachloride-treated mice.","authors":"E Gohda, T Matsunaga, H Kataoka, C Kasada, I Yamamoto","doi":"10.1248/bpb1978.15.131","DOIUrl":"https://doi.org/10.1248/bpb1978.15.131","url":null,"abstract":"<p><p>Mouse hepatocyte growth-stimulating factor (mHGSF), which increased markedly in the liver of carbon tetrachloride-treated mice, was purified 275,000-fold with 21% yield from extracts of the injured liver. The purification involves ammonium sulfate precipitation and chromatography on Affi-Gel Blue, heparin-Sepharose, and S-Sepharose. The purified factor migrated as a major band of 76,000 daltons under nonreducing conditions and two bands of 62,000 and 31,000 daltons under reduced conditions. A dose-response of this growth factor for stimulation of deoxyribonucleic acid synthesis in cultured rat hepatocytes and its maximal effects were similar to those of human hepatocyte growth factor (hHGF), which we previously purified from the plasma of patients with fulminant hepatic failure (E. Gohda et al., J. Clin. Invest., 81, 414-419 (1988)). The effect of mHGSF was additive to the maximal effect of epidermal growth factor and was synergistic with that of insulin or acidic fibroblast growth factor, but was neither additive nor synergistic with the maximal effect of hHGF. mHGSF, like hHGF, was sensitive to heat and trypsin treatments and to reduction by dithiothreitol. This factor did not react with an anti-hHGF antiserum. These results indicate that mHGSF is a hHGF-like factor, but it is immunologically different from hHGF.</p>","PeriodicalId":16743,"journal":{"name":"Journal of pharmacobio-dynamics","volume":"15 3","pages":"131-7"},"PeriodicalIF":0.0,"publicationDate":"1992-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1248/bpb1978.15.131","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12550960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}