Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs from date obtained in in vitro dissolution tests of drug suspensions was studied in the rabbit. The relationship between in vivo and in vitro dissolution rates or between absorption rate and in vitro dissolution rate was investigated. The drug absorption from aqueous solution was suggested to be rate-limited by the gastric emptying rate because the initial absorption rate constant in a biexponential time course of aqueous solution for the amount unabsorbed vs. time plot was almost the same among 9 of the 10 drugs tested, except for sulfacetamide. This indicated that when the in vivo dissolution rate constant is much slower than the initial absorption rate constant of aqueous solution, the time course of blood levels for the solid drug will deviate from that of aqueous solution. Based on the consideration, the critical in vitro dissolution rate constant corresponding to the initial absorption rate constants of aqueous solution was calculated by means of statistical analysis using the relationship between in vivo and in vitro parameters. The validity of this prediction was examined using four high-solubility drugs, and it was found that the prediction could be done whether the in vitro dissolution medium was distilled water or 0.1N HCl solution. Although in the present study, the experiment was done using an aqueous suspension from in the rabbit, the applicability of this prediction method to other dosage forms and to the case of humans is discussed.

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The adenosine cyclic 3', 5' -monophosphate (c-AMP) phosphodiesterase (PDE) inhibitory activity of a series of mesoionic 1, 3, 4- thiadiazolopyrimidines and of a group of benz-fused mesoionic xanthine analogs are found to be significantly correlated with the van der Waals volume (V_w) of the substituents or the first order valence connectivity index (¹X^v) of the molecule. From the correlating equations it is observed that the size of the substituents at certain positions, of pyrimidine ring particularly, in the molecule are determinatitve to the activity. Further based on these equations it may be suggested that PDE inhibition by this class of drugs involves either hydrophobic interaction or van der Waals type of interaction. In certain cases steric and electronic factors are also indicated to affect the inhibition.

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Roles of kininogens in the development of potentiation of carrageenan edema in rats by angiotensin converting enzyme (ACE, = kininase II) inhibitor were studied. Carrageenan-induced edema was potentiated by oral administration of YS980, an ACE inhibitor, at a dose of 1 mg/kg 0.5h before carrageenan injection. Intravenous injection of bromelain, a kininogen (KGN) depletor, at 3 mg/kg produced reduction of plasma KGN (total and high molecular weight KGN), which resulted in suppression of carrageenan edema and suppression of edema potentiation induced by YS980. Even after the plasma KGN level and inflammatory response to carrageenan returned to normal 24h after the administration of bromelain, the potentiative effect of YS980 on the carrageenan edema remained suppressed. Thus, some factor other than plasma KGN is thought to be involved in the potentiation mechanisms on the carrageenan edema by YS980. Partially purified KGN from rat plasma (0.1 mg/ site : liberated 4.4×10_-8g bradykinin eq by trypsin digestion) completely restored the suppressed potentiation to normal by local preinjection to the inflamed site. In addition, such restoration was not observed in the animal in which plasma KGN was reduced 3h after administration of bromelain. These results Suggest that KGN, not only in plasma but also in tissue, play an active role in the development of potentiation of carrageenan edema by ACE inhibitor.

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A simple radioimmunoassay method was established to determine serum levels of a steroidal anti-androgen, TSAA-291 (Oxendolone, 16β-ethyl-17β-hydroxy-4-estren-3-one) utilizing ether-extract of serum. Using an antiserum raised against TSAA-291-3-oxime-BSA conjugate in a rabbit, a standard curve was obtained in the assay range from 30 Pg to 12 ng/tube. Intra- and inter-assay coefficients of variation were calculated to be 11 and 21%, respectively. Recovery rate of unlabeled TSAA -291 was 84%. Cross-reaction with endogenous steroids was less than 0.2%. TSAA-291 estimates were compared with those determined after further purification on a Celite column, or with those assayed with a gas-liquid chromatograph. The difference between these estimates was less than 16 and 25%, respectively, suggesting little contribution of the metabolites of TSAA-291 to the estimates by the radioimmunoassay. After successive treatments of male rats with TSAA-291 in an aqueous suspension in daily doses of 5, 15 and 50 mg/kg body weight for two weeks, Serum TSAA-291 levels were determined by the radio immunoassay and calculated to be 22.7, 76.9 and 194.9 ng/ml, respectively.

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In order to evaluate TEI-4120 (3-benzoyl-N-β-ethoxyisopropyl-2-methylindole), as a possible therapheutic compound to disseminated intravascular coagulation(DIC), DIC model in rats was induced by the treatment of λ-carrageenan according to the method of sugiyama et al. with minor modification. Two hours after intraperitoneal injection of λ-carrageenan, plasma fibrinogen decreased and platelet count, prothrombin time, serial thrombin time and plasma TXB₂ prolonged or increased. By use of this model, the activities of TEI-4120, new antithrombotic compound, was evaluated compared with three other compounds, aspirin, warfarin and heparin. As a result, TEI-4120 is effective in this model. Combination theraphy of TEI-4120 and warfarin is more effective than single administration of TEI-4120. The effect of combination theraphy of TEI-4120 and warfarin is consistene with that of heparin. The above result suggests that TEI-4120 seems to be a promissing compound to the theraphy of DIC.

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In order to estimate the application to rectum of calcium and magnesium salts of indomethacin (IND), the suppositories of the salts and IND were prepared using macrogol and Witepsol H-15 bases. The rectal administration of these suppositories (Witepsol H-15) was compared with the oral administration of IND and the salts. The hardness, melting point, and liquefaction time of the suppositories were similar between IND and the salts. The in vitro release of IND-Mg from the suppositories was significantly faster than that of IND, while the release of IND-Ca was slower. The area under the plasma drug concentration-time curve (AUC) after IND suppositories was significantly higher than that after oral administration of IND (p < 0.01). The AUC value after IND-Ca suppositories was slightly higher than those after other suppositories, although the plasma levels in early period after IND-Ca suppositories were lower, indicating the slow absorption of IND-Ca. The multiple treatment with IND-Ca suppositories gave no histological change of the rectal mucosa. Therefore, the present results suggested that IND-Ca was favourable for the rectal administration, in high doses and repeatedly.

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Non-competitive antispasmodic effects of 8 kinds of synthetic L-α-lysoleci-thins (1-O-acyl-2-lyso- sn -glycero-3-phosphocholine, LPC) with various fatty acid moieties were examined upon the spasmodic actions of histamine and acetylcholine on guinea pig ileum. Five-min pretreatment of the gut with the synthetic LPC was required to be effective. With increase of the concentration of a synthetic LPC for pretreatment of the ileum, the slope of the dose-response curve of histamine or acetylcholine added cumulatively became more gentle, the maximal contraction was suppressed apparently, and which were associated with the shift of the curve to the higher concentration of the stimulants. Of LPCs with saturated fatty acid palmitoyl-LPC showed the strongest effect, followed by myristoyl-, stearoyl-, laurovl- and decanoyl-LPCs in order. Incorporation of cis-double bond into the C₁8 fatty acid chain of LPC resulted in slight decrease of the antispasmodic effect. The relaxating effect of LPCs on perfused rabbit ear vessel preparations was similar in order.

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1- Nitropyrene and nitrofurazone reductases in Escherichia coli B/r were studied comparatively. Nitrofurazone reductase activity was oxygen-insensitive, whereas 1-nitropyrene reductase activity was markedly inhibited by oxygen in both intact cells and cell-free preparations. The former activity depended upon reduced nicotinamide adenine dinucleotide or reduced nicotinamide adenine dinucleotide phosphate, whereas the latter activity upon flavin-adenine dinucleotide (FAD) as well as the reduced pyridine nucleotide. E. coli B/r acquired resistance to nitrofurazone in two mutational steps, associated with stepwise loss of the oxygen-insensitive nitrofuran reductase activity. However, 1-nitropyrene reductases were not affected at all by the mutation. These facts indicated that the major enzymes responsible for the reduction of 1-nitropyrene and nitrofurazone in E. coli B/r were different from each other. 1-Nitropyrene reductases were resolved by diethylaminoethyl-cellulose column chromatography into four enzymes all of which seem to reduce FAD, too. Among them, three enzymes appear to be able also to catalyze the reduction of nitrofurazone under anaerobic conditions.

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The tissue and subcellular distribution of ¹⁴C-2, 3, 4, 7, 8-pentachlorodibenzofuran (PenCDF), one of the most important causal agents of Yusho, were studied using rats. More than 60% of the radioactivity given orally was accumulated in the liver after 5d and this high percentage persisted over a period of 3 weeks. Subcellular fractionation of the liver homogenate showed unusual separation by PenCDF-pretreatment, but the distribution of radioactivity was just parallel to those of cytochrome P-450 content and glucose-6-phosphatase (EC3.1.3.9) activity. Gas chromatographic analysis provided evidence that the extracts from the liver and its subcellular fractionations contained only unchanged PenCDF. Those results strongly suggest that PenCDF has some affinity to endoplasmic reticulum of rat liver.

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The existence of the enterohepatic circulation (EHC) of clioquinol was confirmed by using paired rats, donor and recipient, which were connected to each other with a bile duct-to-duodenum cannula. The concentrations of clioquinol and its metabolites appearing in the plasma of the recipient following intraduodenal 10 mg/kg dose of clioquinol to the donor were fairly low. However, within 24h after the administration ca. 12% of the dose was reexcreted in the bile of the recipient as clioquinol glucuronide and ca.2% in the urine as clioquinol sulfate. From these results and the data of biliary excretion in our previous paper, the glucuronide was found to play a role on the EHC. Further, both in vitro and in situ results suggested that clioquinol glucuronide excreted in the bile may be absorbed partially after return to the parent drug in the intesinal tract and partially as such without deconjugation.

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