ABSTRACT
The interaction between beta-naphthoflavone induction (BNF: 100 mg/kg) and carbon tetrachloride (CCl4; 1 ml/kg) hepatotoxicity was examined in the flounder. Treatment groups composed of control, BNF, CCl4, and BNF/CCl4 were compared in terms of cytochrome P450 isozyme content (LM4b; LM2), catalytic activity, isozyme distribution. SGOT-SGPT levels, and pathology. CCl4 administration resulted in significant reductions in both the constitutive P450 (LM2) and the BNF-inducible isozyme (LM4b) as well as elevations in SGPT and SGOT levels. The decline in LM4b isozyme content was reflected by stoichiometric decreases in ethoxyresorufin-O-deethylase activities. BNF/CCl4 coadministration was protective in part against CCl4 hepatotoxicity. Immunohistochemistry indicated that LM4b was diffusely distributed throughout the liver. These interactions have demonstrated a multiple P450 isozyme involvement, the protective nature of BNF against CCl4 hepatotoxicity in the flounder, the ability to maintain an inductive response in face of CCl4 coadministration, and the diffuse distributional pattern of LM4b in the flounder liver.
Subject(s)
Benzoflavones/pharmacology , Carbon Tetrachloride/toxicity , Cytochrome P-450 Enzyme System/biosynthesis , Flavonoids/pharmacology , Isoenzymes/biosynthesis , Liver/drug effects , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Carbon Tetrachloride/antagonists & inhibitors , Drug Interactions , Enzyme Induction/drug effects , Female , Flounder , Immunoenzyme Techniques , Liver/enzymology , Liver/pathology , Male , Microscopy/methods , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , beta-NaphthoflavoneABSTRACT
1. Uptake, bioavailability, tissue disposition, and elimination of 14C were examined in rainbow trout following intravascular and per os dosing of 14C-ormetoprim (8 mg/kg). 2. Plasma clearance was rapid following a single i.v. dose (t1/2 alpha = 0.54 h, t1/2 beta = 17.5 h) with an apparent volume of distribution (Vss) of 4.85 l/kg. An increase in both t1/2 alpha (0.67 h) and t1/2 beta (36.7 h) was seen following multiple i.v. doses (steady state). 3. Oral dispositional studies revealed the highest concentration of OMP in bile, kidney and liver, indicating significant renal and hepatic extraction. Significant OMP residues were seen in skin (0.90 p.p.m.) and muscle (0.15 p.p.m.) at 38 days. 4. Peak absorption time of orally administered OMP was 12 h with an apparent bioavailability of 87%. 5. Intravascularly administered OMP was 33% and 31% protein-bound at 1 and 6 h respectively, and binding was non-specific and non-saturable by Scatchard analysis.
Subject(s)
Anti-Bacterial Agents , Pyrimidines/pharmacokinetics , Salmonidae/metabolism , Trout/metabolism , Animals , Biological Availability , Carbon Radioisotopes , Half-Life , Kidney/metabolism , Kinetics , Liver/metabolism , Protein Binding , Tissue DistributionABSTRACT
Hepatotoxicity of allyl formate (AF) was studied in trout, to characterize the response of the teleost liver to a mammalian periportal hepatotoxicant. A dose-dependent decrease in liver nonprotein sulfhydryl (NPSH) concentration was observed at 3, 6, and 24 hr following 9.5, 28, and 95 mg/kg) AF with maximal depression seen at 6 hr (51, 40, and 29% control, respectively). Further evidence for glutathione (GSH) protection against AF toxicity was seen when diethylmaleate, a GSH depleting agent (0.6 ml/kg ip), administered 30 min prior to AF (9.5 and 28 mg/kg), increased AF hepatotoxicity (10-fold shift in the dose-response effect on SGPT). Also, N-acetyl-L-cysteine (150 mg/kg ip), a GSH precursor, protected liver against AF toxicity when injected 5 min prior to and 1, 5, and 9 hr after AF (28 and 95 mg/kg). Pyrazole (375 mg/kg ip), an alcohol dehydrogenase inhibitor, given 4 hr before AF (95 mg/kg), attenuated the histopathological effect of AF. These results indicate that AF, once bioactivated by alcohol dehydrogenase, causes significant toxicity in trout liver. GSH protects against AF-induced effects since greater than 50% decreases in liver GSH are required before toxicity is expressed.
Subject(s)
Formates/toxicity , Formic Acid Esters/toxicity , Liver/drug effects , Acetylcysteine/pharmacology , Alanine Transaminase/blood , Aldehyde Dehydrogenase/physiology , Animals , Dose-Response Relationship, Drug , Glutathione/analysis , Glutathione/physiology , Liver/analysis , Maleates/pharmacology , Sulfhydryl Compounds/analysis , TroutABSTRACT
1. Half lives of distribution and elimination phases of 14C-sulfadimethoxine following i.v. dosing of sulfadimethoxine/ormetoprim (SDM/OMP, 42/8 mg/kg) were 0.4 and 16.1 hr respectively. The apparent volume of distribution was 503.9 ml/kg. 2. In vitro plasma protein binding of 14C-SDM was not altered by increasing concentrations of unlabeled OMP. Similarly, binding of 14C-OMP was not altered by SDM. 3. Peak plasma concentrations of 14C-SDM following oral administration of SDM/OMP were observed at 20 hr with an apparent bioavailability of 38%. 4. Oral dispositional studies revealed the highest concentrations of 14C-SDM in bile, intestine, liver and fat. 5. Parent SDM and N-acetylated SDM were detected in plasma from i.v. and orally dosed animals. 6. The pharmacokinetics and distribution of 14C-SDM were not influenced by OMP co-administration.
