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Biomedical subjects

G L Plaa

Publications and source records attributed to G L Plaa.

At least 109 records · Page 6Linked to original sources
PubMed1977

Effects of diazepam on the biliary excretion of diphenylhydantoin in the rat.

Studies were performed to examine the effects of diazepam (DZP) on the biliary excretion of diphenylhydantoin (DPH, phenytoin) in the rat. One-hour pretreatment with DZP (150 mg/kg i.p. or 10 mg/kg i.v.) markedly suppressed the rates as well as the cumulative amounts of radioactivity excreted in bile after administration of 14C-DPH (70, 35 or 10 mg/kg i.v.). No changes in bile flow were apparent and the decreases in biliary excretion were not accompanied by increases in the urinary elimination of the drug or its metabolites. Disappearance of DPH from plasma and tissue were also reduced, and at 4 and 6 hours after DPH administration higher plasma and tissue concentrations were encountered in the DZP-treated group. The possible mechanisms by which DZP pretreatment altered the biliary excretion and the tissue distribution of DPH were examined; studies in vitro were correlated with the in vivo findings. DPH hepatic uptake and storage were apparently unaffected by DZP treatment, but liver/bile concentration ratios were suppressed. However, a direct competition between the two drugs for biliary transport was not evident. Further studies showed that liver microsomes from rats treated with DZP metabolized DPH in vitro less effectively than those from control rats. The metabolism of DPH was more markedly inhibited by the direct addition of DZP to the incubation mixtures in concentrations greater than 0.05 mM. Therefore, it appears that the effect of DZP on the metabolism of DPH is responsible for most of the observed effect although other mechanisms, including a direct effect on hepatocyte function, cannot be completely ruled out.

Animals↗
PubMed1976

The effects of oral diazepam pretreatment on the biliary excretion of sulfobromophthalein in rats.

Studies were performed with rats to examine the effects of single, as well as repetitive oral diazepam (DZP) pretreatment on biliary sulfobromophthalein (BSP) excretion rates and on bile flow parameters. One-hour pretreatment of male rats with 150 mg/kg of DZP resulted in about a one-third reduction in the peak biliary excretion rate of BSP (60 mg/kg, iv) and this was associated with a decrease in relative proportions of conjugated BSP in bile. The biliary excretion of preconjugated BSP was unaffected. BSP hepatic uptake and storage were apparently unaffected. In vitro DZP markedly inhibited BSP conjugating activity. In contrast to the above results, when BSP excretion was examined 1 h after the last of five daily oral doses of DZP (150 mg kg-1 day-1), no change in the peak elimination rate of this dye was evident. However, bile flow rates were higher in DZP-treated rats than in controls. When rats were examined 24 h after the last of five daily oral doses of DZP (150 mg/kg), the choleretic response persisted. Further studies showed that the repetitive DZP pretreatment enhanced the bile salt-independent mechanisms of bile formation.

Animals↗
PubMed1976

The influence of acute diazepam pretreatment on the action and disposition of [14C]pentobarbital in rats.

Diazepam (DZP) pretreatment (100mg/kg, ip) of rats 6 h before pentobarbital administration (45 mg/kg, ip) prolonged the barbiturate-induced narcosis. The concentrations of [14C]pentobarbital and total pentobarbital derivatives in blood or brain showed no differences between control and DZP-pretreated animals. The brain and blood concentrations of pentobarbital, when measured at a time corresponding to the respective arousal times from pentobarbital narcosis, were lower in the DZP-pretreated group. These results indicate that acute DZP pretreatment increases the sensitivity of the rat brain to pentobarbital rather than inducing changes in the disposition of the barbiturate.

Animals↗
PubMed1976

Quantitative aspects in the assessment of liver injury.

Liver function data are usually difficult to use in their original form when one wishes to compare the hepatotoxic properties of several chemical substances. However, procedures are available for the conversion of liver function data into quantal responses. These permit the elaboration of dose-response lines for the substances in question, the calculation of median effective doses and the statistical analysis of differences in liver-damaging potency. These same procedures can be utilized for estimating the relative hazard involved if one compares the liver-damaging potency to the median effective dose for some other pharmacologie parameter. Alterations in hepatic triglycerides, lipid peroxidation, and the activities of various hepatic enzymes can also be quantitiated in a dose-related manner. This permits the selection of equitoxic doses required for certain comparative studies and the selection of doses in chemical interaction studies. The quantitative problems involved in low-frequency adverse reactions and the difficulty these present in the detection of liver injury in laboratory animals are discussed.

1-Propanol↗
PubMed1976

Hepatic function after acute of subchronic nicotine administration in untreated mice and mice treated with hepatotoxic chemicals.

Male mice treated with nicotine hydrochloride either acutely (5 mg/kg i.p.) or subchronically (5 mg/kg i.p. daily for 3 weeks; 25 mg/liter in drinking water for 2-3 months) showed no evidence of hepatic dysfunction, as measured by serum glutamic-pyruvic transaminase or serum alkaline phosphatase activities. Neither acute nor subchronic administration modified the hepatotoxic response to a potent hepatotoxin (carbon tetrachloride), nor that of less potent hepatotoxins chloroform or 1, 1, 1-trichloroethane, nor was the cholestatic effect of alpha-naphthylisothiocyanate modified.

1-Naphthylisothiocyanate↗
PubMed1975

Potentiation of the hepatotoxic responses to chemicals in alloxan-diabetic rats.

Alloxan diabetes enhances the hepatotoxic response of male rats to chloroform and 1, 1, 2-trichloroethane, but not to trichloroethylene nor 1, 1, 1-trichloroethane. Insulin treatment partially protects the animals against the alloxan-induced enhancement of chloroform hepatotoxicity. Alloxan diabetes also enhances the hepatotoxic response to galactosamine but not to beryllium nor alpha-naphthylisothiocyanate.

1-Naphthylisothiocyanate↗
PubMed1975

Metabolic alterations in organ function.

When the standardization of procedures is envisioned, problems arise regarding the selection of the test procedure and its ability to detect changes in organ function. Dose-response curves can be derived for the parameters used for assessing dysfunction. These curves can be useful for selecting equitoxic doses of substances to be compared with each color. They can also be useful for estimating relative safety as well as absolute toxic potency. Enzyme inducers can be used to determine whether metabolic transformations are involved in toxic reactions. However, all enzyme inducers do not produce the same effect. It is necessary to clearly define the enzyme inducers that have to be employed. Interactions leading to enhanced toxic effects can occur by pathways other than enzyme induction. It is necessary to determine if the toxic interaction is the result of a change in the sensitivity of the organ to the presence of the toxic moiety. The experimental environment can also affect toxicity. The presence of pathology in laboratory animals may alter the response. Body temperature can also markedly alter the response to a toxic agent.

Animals↗
PubMed1975

Potentiation of carbon tetrachloride-induced hepatotoxicity in alloxan- or strepto- zotocin-diabetic rats.

Studies were performed to examine the effects of alloxan- or streptozotocin-induced diabetes on carbon tetrachloride (CCl4) liver injury. Male rats were pretreated with single i.v. injections of alloxan monohydrate (40 or 80 mg/kg) or streptozotocin (65 mg/kg). A challenging dose of CCl4 (0.1 ml/kg i.p.) was given to rats 4 days after alloxan pretreatment or 5 days after streptozotocin pretreatment, and the animals were sacrificed 24 hours later. Biochemical and morphologic evidence was obtained to show that pretreatment with the diabetogenic agents markedly enhanced CCl4-induced hepatotoxity. The challenging dose of CCl4 had no effect on the serum glutamic pyruvic transaminase (SGPT) activity in control rats. However, the administration of this dose of CCl4 to rats pretreated with 40 and 80 mg/kg of alloxan as well as to rats pretreated with streptozotocin resulted in 11-, 68-, and 32-fold increases, respectively, in SGPT activity. Hepatic triglyceride concentrations in the diabetic rats were also markedly elevated above control values after CCl4 challenge. Alloxan- or streptozotocin-pretreatment alone did not enhance these biochemical parameters of liver injury. Hepatic glucose-6-phosphatase activity, which increased in the rats given a diabetogenic agent, was lowered as a result of CCl4 injection. Insulin treatment of rats given alloxan (80 mg/kg) markedly protected against CCl4-induced hepatotoxicity. The severity of the morphologic changes in diabetic rats given CCl4 correlated with the biochemical findings.

Alanine Transaminase↗