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The effect of ascorbic acid nutritional status on paraquat toxicity in guinea pigs
131 EFFECT OF HALOTHANE, BINDING OF DRUGS.
ENFLURANE
AND
THEIR
UET’ABOLITES
ON THE SERUM PROTEIN
DALE, 0. and NILSEN, 0-G. DEPT. OF PHARMACOLOGY AND TOXICOLOGY SCHOOL OF MEDICINE, UNIVERSITY OF TRONOHEIM N-7000 TRONDHEIM, NORWAY
Inhaled volatile
and their mctabolites might influence xenobiotic pharmaco/toxicokinexenobiotic metabolizing enzymes, but also by changing the serum protein
anesthetics
tics not only by affecting
binding of the xenobiotic in question. lialothane and its met&o&es trifluoroacetic acid fTFA) and bromide, and enflurane and its metabolitc fluoride were investigated with respect to their ability to alter the serum protein binding of prazosin, propranolol, diazepam and phenytoin. The binding was determined in vitro by equilibrium dialysis. pH was controlled before and after dialysis. The free fractions of the acidic drug ~ny~~ end the basic drug diazepam, both mainly bound to albumine, were increased in the presence of TFA (0.540 mmof/l). The serum protein binding of the
basic drugs prazosin and propranolol with al-acid glycoprotein as an important binding protein, was unaffected by the presence of TFA. Equilibrium dialysis performed in an atmosphere of halothane (2.5%) and enflurane (5%) Produced results similar to those described for TFA. No changes were observed in the serum protein binding in the presence of bromide and fluoride (Z-20 mmol/& It is concluded that halothane anesthesia by the metabolite TFA can affect the pharmaco/toxicokinetics of drugs mainly bound to albumine, whereas basic drugs mainly bound to al -acid glycoprotein are unaffected. The resuits indicate further that unmetaboIized haiothane and enfiurane in high concentrations may interact with the drug binding properties of albumine, but probably not with those of a 1 acid glycoprotein.
THE EFFECT OF ASCORBIC ACID NUTRITIO~L STATUS ON P~QUAT
SULLIVAN,T. M., AND MONTGOMERY,M. R. STREET,TAMPA, FLORIDA 33612 USA.
TOXICITY IN GUINEA PIGS
VETERANSADMINISTRATIONHOSPITAL,13000 NORTH 3OTH
The Effect of AscorbicAcid NutritionalStatus on ParaquatToxicity in Guinea Pigs. Sullivan,T. M., and Montgomery,M. R. VA Hospitaland Dept. of Pharmacol.,Univ. of South Florida,Tampa, FL 33612 USA. Ascorbic acid (ASA) has been consideredin treatmentof paraquat (Pq) i!-toxication. However,several reports of in vitro ASCA effects on Pq toxicityhave indica,euthat AscA actions of Pq which lead to pulmonarytoxicmay potentiatePq toxicity,?hxchemical ity are presumed to occur within hours of the poisoning. Hence, if AscA effects are significant;endogenousrather than administeredkcA will play the major role. Therefore, male guinea pigs _ - were maintainedon diets with controlledAscA levels for 14 days before receivingPq. AscA was added to ascorbatedeficientguinea pig diets at levelsof 0. 1, and 20 glkg of diet. The AscA concentrationsin the lungs averaged 3.2, 255, and 331 ug/g for the 0, 1, and 20 g ascorbatefkgdiet group animals,respectively,after 14 days Pq was administeredip and several parametersof Pq toxicitywere of dietary treatment. measured. The distributionof 146 was determinedat 6 and 24 hr after 14C-Pq doses of 2 Covalentbinding in lung and liverwas determined6 and 24 hr after and 20 mg base/kg. doses of 20 mg base/kg. A dose of 10 mg base/kgwas used to increase the thiobarbituric acid (TBA) reactivityof lung homogenatesas an index of in viva lipid peroxidation. The distributionof 14C was not affected by diet at either sazi= time for any dose. Specifically,lung concentrationswere not affected. A low level of 14C activitywas assoThe amount of bound 14~ activity ciated with exhaustively extracted protein precipitates. did not differ among the diet groups. The T8A reactivityuf lung homogenateswas increased by Pq equally in all three diet groups, although the scorbuticlungs had dramatically increasedcontrol levels of TBA reactivity. AscA nutritionalstatus had no significant effect beneficialor detrimental,on these parametersof Pq toxicity. Supportedby VA Medical Research Funds and NIH Grant ES02846.
ENFLURANE
AND
THEIR
UET’ABOLITES
ON THE SERUM PROTEIN
DALE, 0. and NILSEN, 0-G. DEPT. OF PHARMACOLOGY AND TOXICOLOGY SCHOOL OF MEDICINE, UNIVERSITY OF TRONOHEIM N-7000 TRONDHEIM, NORWAY
Inhaled volatile
and their mctabolites might influence xenobiotic pharmaco/toxicokinexenobiotic metabolizing enzymes, but also by changing the serum protein
anesthetics
tics not only by affecting
binding of the xenobiotic in question. lialothane and its met&o&es trifluoroacetic acid fTFA) and bromide, and enflurane and its metabolitc fluoride were investigated with respect to their ability to alter the serum protein binding of prazosin, propranolol, diazepam and phenytoin. The binding was determined in vitro by equilibrium dialysis. pH was controlled before and after dialysis. The free fractions of the acidic drug ~ny~~ end the basic drug diazepam, both mainly bound to albumine, were increased in the presence of TFA (0.540 mmof/l). The serum protein binding of the
basic drugs prazosin and propranolol with al-acid glycoprotein as an important binding protein, was unaffected by the presence of TFA. Equilibrium dialysis performed in an atmosphere of halothane (2.5%) and enflurane (5%) Produced results similar to those described for TFA. No changes were observed in the serum protein binding in the presence of bromide and fluoride (Z-20 mmol/& It is concluded that halothane anesthesia by the metabolite TFA can affect the pharmaco/toxicokinetics of drugs mainly bound to albumine, whereas basic drugs mainly bound to al -acid glycoprotein are unaffected. The resuits indicate further that unmetaboIized haiothane and enfiurane in high concentrations may interact with the drug binding properties of albumine, but probably not with those of a 1 acid glycoprotein.
THE EFFECT OF ASCORBIC ACID NUTRITIO~L STATUS ON P~QUAT
SULLIVAN,T. M., AND MONTGOMERY,M. R. STREET,TAMPA, FLORIDA 33612 USA.
TOXICITY IN GUINEA PIGS
VETERANSADMINISTRATIONHOSPITAL,13000 NORTH 3OTH
The Effect of AscorbicAcid NutritionalStatus on ParaquatToxicity in Guinea Pigs. Sullivan,T. M., and Montgomery,M. R. VA Hospitaland Dept. of Pharmacol.,Univ. of South Florida,Tampa, FL 33612 USA. Ascorbic acid (ASA) has been consideredin treatmentof paraquat (Pq) i!-toxication. However,several reports of in vitro ASCA effects on Pq toxicityhave indica,euthat AscA actions of Pq which lead to pulmonarytoxicmay potentiatePq toxicity,?hxchemical ity are presumed to occur within hours of the poisoning. Hence, if AscA effects are significant;endogenousrather than administeredkcA will play the major role. Therefore, male guinea pigs _ - were maintainedon diets with controlledAscA levels for 14 days before receivingPq. AscA was added to ascorbatedeficientguinea pig diets at levelsof 0. 1, and 20 glkg of diet. The AscA concentrationsin the lungs averaged 3.2, 255, and 331 ug/g for the 0, 1, and 20 g ascorbatefkgdiet group animals,respectively,after 14 days Pq was administeredip and several parametersof Pq toxicitywere of dietary treatment. measured. The distributionof 146 was determinedat 6 and 24 hr after 14C-Pq doses of 2 Covalentbinding in lung and liverwas determined6 and 24 hr after and 20 mg base/kg. doses of 20 mg base/kg. A dose of 10 mg base/kgwas used to increase the thiobarbituric acid (TBA) reactivityof lung homogenatesas an index of in viva lipid peroxidation. The distributionof 14C was not affected by diet at either sazi= time for any dose. Specifically,lung concentrationswere not affected. A low level of 14C activitywas assoThe amount of bound 14~ activity ciated with exhaustively extracted protein precipitates. did not differ among the diet groups. The T8A reactivityuf lung homogenateswas increased by Pq equally in all three diet groups, although the scorbuticlungs had dramatically increasedcontrol levels of TBA reactivity. AscA nutritionalstatus had no significant effect beneficialor detrimental,on these parametersof Pq toxicity. Supportedby VA Medical Research Funds and NIH Grant ES02846.