Metabolism of daunorubicin by a barbiturate-sensitive aldehyde reductase from rat liver.
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A barbiturate-sensitive aldehyde reductase was purified to homogeneity from rat liver and shown to metabolize the cancer-chemotherapeutic antibiotic daunorubicin. The aldehyde reductase may have important roles in the metabolism of exogeneous drugs as well as the aldehyde derivatives of the biogenic amines. (+info)
Mouse popliteal lymph node assay for assessment of allergic and autoimmunity-inducing potentials of low-molecular-weight drugs.
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In the present collaborative study, popliteal lymph node (PLN) responses to penicillin G (an allergenic chemical), D-penicillamine (an autoimmunity-inducing chemical), and barbital (a negative reference chemical) were investigated in three different mouse strains by ten pharmaceutical companies. Two inbred mouse strains (BALB/c and A/J) and one outbred strain (ICR) were subcutaneously injected with saline solutions containing penicillin G (1.25, 2.5 and 5 mg/mouse), D-penicillamine (0.5, 1 and 2 mg/mouse), or barbital (2 mg/mouse) into one hind footpad and saline only was injected into the contralateral footpad. PLN cellularity indices were determined on day 7. In the three strains tested, the penicillin G and D-penicillamine injections resulted in approximately dose-dependent responses. In contrast, barbital failed to generate a significant PLN reaction. In the typical data from one of the participating laboratories, the PLN responses of A/J, BALB/c, and ICR to penicillin G were high, intermediate and low, respectively, while their PLN responses to D-penicillamine were all high. Some variation in PLN cellularity indices was observed among the participating laboratories, but reproducibility of the popliteal lymph node assay (PLNA) evaluation was partly confirmed. Although the appropriate selection of mouse strains and drug dosage levels has to be considered, these results suggest that the PLNA may be an appropriate screening system for prediction of the allergic or autoimmunity-inducing potentials of low-molecular-weight drugs. (+info)
Apoptosis and cell proliferation in rat hepatocytes induced by barbiturates.
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To examine the effect on cell population in hepatocytes of phenobarbital (PB) and other barbiturates, PB, allobarbital (ALB), barbital sodium (BS) and barbituric acid (BA) were given orally to male rats for 7 consecutive days. Although there was no apparent change in non-promoting BA, hepatomegaly was induced by PB, BS and ALB, which are promoters of hepatocarcinogenesis. In PB- and BS-treated livers, hepatomegaly was attributable to hepatocyte proliferation and enzyme induction. In ALB-treated liver, it was attributable to enzyme induction. The level of cell proliferation was reduced to less than the control values following withdrawal of PB, ALB and BS. It seemed that the degree of suppression of cell proliferation following withdrawal of these compounds correlated to the degree of cell proliferation (PB>BS>ALB) during treatment. In PB-treated liver, apoptosis was induced during treatment, serving to eliminate the excess of hepatocytes. This suggests that short-term administration of PB neither induced suppression of apoptosis nor disturbed homeostasis of hepatocyte populations. (+info)
Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats.
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Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration-response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m. A second study was conducted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model. (+info)
Effect of nonionic surfactant on transport of surface-active and non-surface-active model drugs and emulsion stability in triphasic systems.
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The effect of surfactant concentration on transport kinetics in emulsions using surface-active (phenobarbital, barbital) and non- surface-active (phenylazoaniline, benzocaine) model drugs is determined. Mineral oil was chosen as the oil phase and the nonionic surfactant polyoxyethylene-10-oleyl-ether (Brij 97) was chosen as the emulsifier. Model drug transport in the triphasic systems was investigated using side-by-side diffusion cells mounted with hydrophilic dialysis membranes (molecular weight cutoffs 1 kd and 50 kd) and a novel bulk equilibrium reverse dialysis bag technique. Emulsion stability was determined by droplet size analysis as a function of time, temperature, and the presence of model drugs, using photon correlation spectroscopy. Mineral oil/water (O/W) partition coefficients and aqueous solubilities were determined in the presence of surfactant. The transport rates of model drugs in emulsions increased with an increase in Brij 97 micellar concentrations up to 1.0% wt/vol and then decreased at higher surfactant concentrations. The transport profiles of the model drugs appeared to be governed by model drug O/W partition coefficient values and by micellar shape changes at higher surfactant concentrations. Total transport rates of phenobarbital and barbital were faster than those of phenylazoaniline and benzocaine. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug surface activity and lipophilicity. (+info)
Mathematical modeling of surface-active and non-surface-active drug transport in emulsion systems.
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Mathematical models were developed for the prediction of surface-active and non- surface-active drug transport in triphasic (oil, water, and micellar) emulsion systems as a function of micellar concentration. These models were evaluated by comparing experimental and simulated data. Fick's first law of diffusion with association of the surface-active or complexation nature of the drug with the surfactant was used to derive a transport model for surface-active drugs. This transport model assumes that the oil/water (O/W) partitioning process was fast compared with membrane transport and therefore drug transport was limited by the membrane. Consecutive rate equations were used to model transport of non-surface-active drugs in emulsion systems assuming that the O/W interface acts as a barrier to drug transport. Phenobarbital (PB) and barbital (B) were selected as surface-active model drugs. Phenylazoaniline (PAA) and benzocaine (BZ) were selected as non- surface-active model drugs. Transport studies at pH 7.0 were conducted using side-by-side diffusion cells and bulk equilibrium reverse dialysis bag techniques. According to the surface-active drug model, an increase in micellar concentration is expected to decrease drug-transport rates. Using the Microsoft EXCEL program, the non-surface-active drug model was fitted to the experimental data for the cumulative amount of the model drug that disappeared from the donor chamber. The oil/continuous phase partitioning rates (k1) and the membrane transport rates (k2) were estimated. The predicted data were consistent with the experimental data for both the surface-active and non- surface-active models. (+info)
Rapid stimulation of free glucuronate formation by non-glucuronidable xenobiotics in isolated rat hepatocytes.
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Vitamin C synthesis in rat liver is enhanced by several xenobiotics, including aminopyrine and chloretone. The effect of these agents has been linked to induction of enzymes potentially involved in the formation of glucuronate, a precursor of vitamin C. Using isolated rat hepatocytes as a model, we show that a series of agents (aminopyrine, antipyrine, chloretone, clotrimazole, metyrapone, proadifen, and barbital) induced in a few minutes an up to 15-fold increase in the formation of glucuronate, which was best observed in the presence of sorbinil, an inhibitor of glucuronate reductase. They also caused an approximately 2-fold decrease in the concentration of UDP-glucuronate but little if any change in the concentration of UDP-glucose. Depletion of UDP-glucuronate with resorcinol or d-galactosamine markedly decreased the formation of glucuronate both in the presence and in the absence of aminopyrine, confirming the precursor-product relationship between UDP-glucuronate and free glucuronate. Most of the agents did not induce the formation of detectable amounts of glucuronides, indicating that the formation of glucuronate is not due to a glucuronidation-deglucuronidation cycle. With the exception of barbital (which inhibits glucuronate reductase), all of the above mentioned agents also caused an increase in the concentration of ascorbic acid. They had little effect on glutathione concentration, and their effect on glucuronate and vitamin C formation was not mimicked by glutathione-depleting agents such as diamide and buthionine sulfoximine. It is concluded that the stimulation of vitamin C synthesis exerted by some xenobiotics is mediated through a rapid increase in the conversion of UDP-glucuronate to glucuronate, which does not apparently involve a glucuronidation-deglucuronidation cycle. (+info)
Counterimmunoelectrophoresis of pneumococcal antigens:improved sensitivity for the detection of types VII and XIV.
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Rapid identification of Streptococcus pneumoniae has been reported using counterimmunoelectrophoresis for the detection of specific capsular antigens in serum, cerebrospinal fluid, and urine. Previous clinical studies have failed to detect type VII or XIV pneumococcal antigen. These two types, however, account for a significant portion of pneumococcal disease. The incorporation of a sulfonated derivative of phenylboronic acid in the buffer system provides a method for the sensitive detection of these types in artificial mixtures without greatly reducing the sensitivity for the detection of other pneumococcal types. A problem with false positives encountered using human serum and barbitalbuffer was reduced by the use of buffer containing sulfonated phenylboronic acid. (+info)