To clarify the interaction between valproic acid (VPA) and anticonvulsive drugs such as phenytoin (DPH), phenobarbital (PB) and carbamazepine (CBZ), the effects of these anticonvulsants on the plasma levels and enterohepatic circulation of VPA and on drug metabolizing enzyme activities in liver in relation to their inductive effects were investigated in rats. After intravenous (i. v.) or oral administration, plasma VPA rapidly decreased, and this was followed by a secondary increase in plasma level of VPA due to enterohepatic circulation. When the drug was repeatedly coadministered with DPH or CBZ, the initial VPA elimination from plasma up to 1 h after dosing was less than with VPA alone, while PB significantly enhanced the disappearance of VPA. Judging from the decrease in the area under plasma VPA concentration-time curve from 2 to 9 h (AUC_2-9), the enterohepatic circulation of VPA was also decreased by PB, but not by DPH and CBZ. The in vitro and in vivo protein binding of VPA was almost unchanged in the presence of DPH. Cytochrome P-450 content and glucuronyltransferase activity were enhanced following repeated coadministration with PB, DPH or CBZ. These enzyme activities in the animals treated with VPA alone at various dosage levels, however, remained unchanged, indicating that VPA did not inhibit the hepatic drug metabolizing enzyme activities in rats.

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In an attempt to explore the quantitative relation in the intestinal absorption between in vivo and a perfusion system, time courses of the remaining fraction in the stomach and that in the small intestine following the intragastric administration of drug solution to rats were simultaneously analyzed by a linear compartment model, using L-glucose and 3-O-methyl-D-glucose (3-O-MG) as model compounds. Derived first-order gastric emptying rate constant (k_g) and first-order intestinal absorption rate constant (k_a) were 0.025 and 0.018 min^-1, respectively, for L-glucose and 0.033 and 0.275 min^-1, respectively, for 3-O-MG. Values of the membrane permeability clearance (CL_{a, m}) estimated in the perfusion system were 0.71 and 3.00 μl/min/cm, respectively, for L-glucose and 3-O-MG. The operational luminal volume (V_o), given as CL_{a, m}/k_a, of 39 μl/cm for L-glucose was in agreement with the actual luminal volume in vivo estimated by a inulin dilution method and ranging from 20 to 60 μl/cm, supporting the idea that CL_{a, m} quantitatively reflects the intestinal membrane permeability in vivo and that the luminal volume in vivo is the primary factor which correlates CL_{a, m} and K_a. The V_o of 11 μl/cm for 3-O-MG was smaller, though still in the same order. It was also shown that the gastrointestinal absorption of 3-O-MG was gastric emptying limited.

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From the standpoint of utilizing the distinctive feature of para-aminobenzoic acid (PABA) and the metabolism of intestinal bile acid, a conjugate of ursodeoxycholic acid with PABA (PABA-UDCA) was newly synthesized to study whether it can be a good material or not for the evaluation of the activity of intestinal bacterial growth. This compound was efficiently deconjugated in an incubation experiment with cholylglycine hydrolase resulting in the release of PABA. In a cultivation experiment, this compound was deconjugated by the same species of aerobic and anaerobic bacteria that deconjugated glycocholic acid. In an animal experiment, urinary excretions of PABA during 6 h following oral administration of 10 mg PABA-UDCA were determined. The control rats (n=10) excreted 338.5±13.8μg (mean±S.E.) of PABA. In contrast with this, the rats (n=10) with intestinal antisepsis by the administration of polymyxin B and tinidazole excreted less PABA (14.0±2.5 μg ; p<0.001), whereas the rats with intestinal bacterial overgrowth owing to the artificially made enteric blind loop excreted more PABA than the control rats did (673.6±70.2 μg ; p<0.01). These observations indicate that this new compound is likely to offer a simple and rapid method for evaluation of intestinal bacterial growth.

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This study was aimed to clarify the fate of the perfused drug and the characteristics of the serosal compartment. A portion of rat small intestine immersed in a solution regarded as the serosal compartment was perfused in situ and the permeability of drugs into the mesenteric venous blood and into the serosal solution were determined. The cumulative amounts of salicylamide (SAM) transported to the mesenteric venous blood and the serosal compartment were 19.7 and 45.8% of amount disappeared from the intestinal lumen, respectively and those of benzoic acid (BA) were 47.4 and 12.7%, respectively. The permeability of SAM into the serosal compartment was 2.8 times of that into the mesenteric venous blood, while the permeability of BA into the serosal compartment was only one fourth of that into the mesenteric venous blood.

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Like human kininogens-deficiency, the ureter urine of Brown Norway (B/N) Katholiek rat, a congenitally deficient strain in plasma high molecular weight (HMW)-and low molecular weight (LMW)-kininogen, showed no detectable kinin in the peptide fraction of gel chromatography, whereas normal ureter urine (B/N-Kitasato rat) expressed kinin in the peptide fraction, when assayed by bradykinin enzyme immunoassay (EIA). However there was immunoreactive substance in the higher molecular weight fraction in both strains of rat. The nature of this substance is not known, but it may give rise to a wrong estimate for kinin if rat urine is allowed to immunoassay directly, and peptide fraction of urine is not resolved into its components by gel chromatography. Kinin degrading activity in rat urine is so potent that kinin could be mostly degraded when stored in the bladder, since kinin was found in the peptide fraction of fresh ureter urine but not in that of bladder urine of the normal strain.

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The effects of structure around the 3-and 5-alkoxycarbonyl groups and the 2-carbamate groups of 4-(2, 3-dichlorophenyl)-2-carbamoyloxymethyl dihydropyridine derivatives were investigated, concerning their vasodilating action, plasma level, hypotensive action and acute toxicity. High negative linear correlation was found between the plasma levels and the number of C atoms in esterifying alkyl groups in 3-and 5-positions of the dihydropyridine ring. High plasma levels and effective hypotensive action were found in compounds having lower alkyls as esterifying groups of 3- and 5-carboxylgroups, among 2-unsubstituted derivatives.

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An in vitro examination was made of the synergistic antiproliferative effect of recombinant interferon-γ (IFN-γ) with interferon-α_2a (IFN-α_2a) on human tumor cell lines, including lung small cell carcinoma QG-90, amelanotic melanoma HMV-1, renal carcinoma ACHN and Burkit lymphoma Daudi. Sixty-four percent of HMV-1 cells and 75% of ACHN cells seeded were killed by treatment with 10 pM and 1000 pM of IFN-γ, respectively. Furthermore, 69% of HMV-1 cells and 59% of ACHN cells were killed by 1000 pM of IFN-α_2a. When HMV-1 was treated first with 10 pM of IFN-γ, and then with 1000 pM of IFN-α_2a, 81% of cells seeded were killed (p<0.001). Similarly, 89% of ACHN cells were killed by the same sequential treatment with 1000 pM of IFN-γ, and then of IFN-α_2a (p<0.001). However, adverse sequence of treatment could not produce such a synergistic result. On the surface of these susceptible cells, HMV-1 and ACHN, to both IFNs, the number of receptors for IFN-α_2a increased significantly after treatment with IFN-γ without any serious change of the dissociation constant, suggesting that increase in the number of receptors for IFN-α_2a may be the major mechanism of the synergistic effects of IFN-γ with IFN-α_2a.

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Hooded Gunn rats which have low-activity of 4-nitrophenol uridine diphosphate-glucuronosyltransferase (GT) and defect in bilirubin GT were crossed with albino LA Wistar rats with a defect in androsterone GT. From F₂ and F₃ progeny were selected Gunn-LA Wistar rats which have defective bilirubin and androsterone GTs and low-active 4-nitrophenol GT. These rats had either hooded or albino coat color. In order to establish a uniform genetic background, albino male Gunn-LA Wistar rats were crossed with heterozygous albino female Gunn-LA Wistar rats in terms of bilirubin GT. The offsprings were all albino and were classified to Gunn-LA Wistar rats and heterozygous Gunn-LA Wistar rats by assaying their hepatic GT activities or by the appearance of jaundice. The linkage relationships between GT and coat color genes are discussed.

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