Edward J. Flynn
Rutgers University
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Drug and Chemical Toxicology | 2000
Gina M. Pastino; Edward J. Flynn; Lester G. Sultatos
Chronic exposure to excessive ethanol consumption has adverse effects on virtually all organs and tissues in the body, including but not limited to the liver, pancreas, reproductive organs, central nervous system, and the fetus. Exposure to ethanol can also enhance the toxicity of other chemicals. Not all persons exposed to the same amount of ethanol experience the same degree of adverse effects. For example, only 12% to 13% of alcohol abusers develop cirrhosis. Possible factors which may alter susceptibility include age, sex, nutritional status, health status (i.e., smokers) and race. Some of these factors affect susceptibility because they alter ethanol metabolism, which occurs primarily in the liver by alcohol dehydrogenase (ADH). Genetic polymorphisms for ADH partially account for the observed differences in ethanol elimination rates among various populations but the relative contribution to susceptibility is not completely understood. Incorporation of the kinetic parameters associated with ADH polymorphisms into a physiologically based pharmacokinetic (PBPK) model for ethanol will aid in assessing the relative contribution to susceptibility. The specific information required to develop this model includes Km and Kcat values for each ADH isoform and the amount of each isoform present in the liver. Blood ethanol concentrations (BEC) from various populations with known ADH phenotypes are also necessary to validate the model. The impact of inclusion of these data on PBPK model predictions was examined using available information from adult white and African American males.
European Journal of Pharmacology | 1977
Edward J. Flynn; Kenneth V. Cerreta; Sydney Spector
Rabbits were actively immunized using a barbiturate--BGG conjugate as the immunogen. The antiserum obtained from actively immunized rabbits was administered intravenously to mice to accomplish passive immunization. The antibody binding capacity for 3H-phenobarbital was shown to be sustained in passively immunized mice for periods of up to three weeks. Serum levels of 3H-phenobarbital in passively immunized mice and control mice were compared following drug administration and found to be altered in the antibody-containing mice. There was a 4-fold higher amount of 3H-phenobarbital present in the serum of passively immunized mice compared to control animals. The higher barbiturate levels were due to binding of 3H-phenobarbital to globulin fraction of serum in passively immunized mice. Additionally, decreased pentobarbital-induced ataxia was demonstrated in passively immunized mice. The decreased responsiveness was selective for barbiturates in passively immunized mice and did not modify the ataxia produced in these animals by another depressant agent, ethanol.
Brain Research | 1995
Tracy Brightman; Jiang Hong Ye; Elizabeth Ortiz-Jimenez; Edward J. Flynn; Wen-hsien Wu; Joseph J. McArdle
While adult mice receiving picrotoxin (PTX) alone responded with clonic and tonic-clonic seizures, this response was greatly suppressed for mice simultaneously injected with 2,3-butanedione monoxime (BDM). For example, 60% and 10% of the mice convulsed when injected (i.p.) with 3.0 mg/kg PTX alone or PTX plus 205 mg/kg of BDM, respectively. In contrast, a non-oxime analogue of BDM, 2,3-butanedione (BTD), did not have this anticonvulsant effect. In order to explore the basis for the anticonvulsant effect of BDM, we recorded GABA-activated currents (IGABA) of frontal cortical as well as ventromedial hypothalamic neurons before, during and after exposure to this oxime. BDM had a biphasic effect on IGABA. That is, high concentrations (100 microM-40 mM) decreased and lower concentrations (0.01 microM-0.001 microM) potentiated IGABA; these effects of BDM reversed upon washout of the oxime. In contrast, BTD had no effect on IGABA. Finally, when 0.001 microM BDM, 10-30 microM PTX and GABA were co-applied the inhibitory effect of the toxin on IGABA was markedly suppressed. These data suggest that the anticonvulsant effect of oximes involves facilitation of the inhibitory action of GABA.
Clinical Immunology and Immunopathology | 1977
Kenneth V. Cerreta; Edward J. Flynn; Sydney Spector
Abstract Antibodies have been produced in mice by immunization with 5-allyl-5-(β-carboxyl-α-methylethyl) barbituric acid-bovine γ-globulin (BGG) as the antigen. Antibody production develops over a period of 3 months and is related to the number of booster injections of antigen. The immunization schedule elicits antibody production in mice, which varies from mouse to mouse, and sera from these animals bind [3H]phenobarbital in vitro while control sera do not. It has been demonstrated that the globulin factor responsible for [3H]phenobarbital binding is of the immunoglobulin G class. Specificity studies demonstrated that the antibodies require an unsubstituted urea portion of the barbiturate ring for recognition. A variety of substitutions can be made at carbon 5 without destroying the binding of the compound to the antibody; however, the relative affinity of the derivative for the antibody is modified. The disposition of [3H]phenobarbital in actively immunized mice was altered compared to control animals. There was a threefold higher amount of [3H]phenobarbital present in the serum and a longer biological half-life ( t 1 2 ) in actively immunized mice than in control mice. The increase in barbiturate level was due to the presence of immunoglobulin G.
Clinical Immunology and Immunopathology | 1978
Edward J. Flynn; Kenneth V. Cerreta
Abstract Mice were actively immunized by administration of a barbiturate conjugated to bovine γ-globulin. The immunization procedure resulted in production of an immunoglobulin G specific for barbiturates and which in vivo resulted in increased serum levels of [ 3 H]phenobarbital following drug administration. The absolute magnitude of the higher drug levels was directly related to antibody-binding capacity. The binding of [ 3 H]phenobarbital to antibody prevented participation of the drug in normal distribution and metabolic and excretory processes, thereby prolonging its half-life.
Regulatory Toxicology and Pharmacology | 2003
G.M. Pastino; A.A. Kousba; Lester G. Sultatos; Edward J. Flynn
An approach for deriving occupational exposure limits (OEL) for pharmaceutical compounds is the application of safety factors to the most appropriate pre-clinical toxicity endpoint or the lowest therapeutic dose (LTD) in humans. Use of this methodology can be limited when there are inadequate pre-clinical toxicity data or lack of a well-defined therapeutic dose, and does not include pharmacokinetic considerations. Although some methods have been developed that incorporate pharmacokinetics, these methods do not take into consideration variability in response. The purpose of this study was to investigate how application of compartmental pharmacokinetic modeling could be used to assist in the derivation of OELs based on target blood concentrations in humans. Quinidine was used as the sample compound for the development of this methodology though the intent was not to set an OEL for quinidine but rather to develop an alternative approach for the determination of OELs. The parameters for the model include body weight, breathing rate, and chemical-specific pharmacokinetic constants in humans, data typically available for pharmaceutical agents prior to large scale manufacturing. The model is used to simulate exposure concentrations that would result in levels below those that may result in any undesirable pharmacological effect, taking into account the variability in parameters through incorporation of Monte Carlo sampling. Application of this methodology may decrease some uncertainty that is inherent in default approaches by eliminating the use of safety factors and extrapolation from animals to humans. This methodology provides a biologically based approach by taking into consideration the pharmacokinetics in humans and reported therapeutic or toxic blood concentrations to guide in the selection of the internal dose-metric.
Human and Ecological Risk Assessment | 2004
G.M. Pastino; Lester G. Sultatos; Edward J. Flynn
ABSTRACT The purpose of this study was to investigate how variability in pharmacokinetic parameters influences the determination of occupational exposure limits (OEL) for pharmaceutical compounds in potentially susceptible subpopulations. A compartmental pharmacokinetic model for quinidine was applied to derive OELs based on target blood concentrations in humans but relied on pharmacokinetic parameters in subjects with cirrhosis rather than normal subjects. Quinidine was used as the sample compound as this was used in the development of the methodology. The intent was not to set an OEL for quinidine for a particular population but rather to use the methodology to investigate how factors, which may influence susceptibility, could be incorporated into the analysis. The model was used to simulate exposure concentrations that would result in levels below those that cause undesirable pharmacological effects taking into account variability in parameters through incorporation of Monte Carlo sampling. Results indicate that cirrhotic patients did not require additional protection from occupational exposure to quinidine. These results cannot be extrapolated to other compounds, as the effects of variability in pharmacokinetics on systemic exposure are compound specific. However, this methodology does provide a framework for addressing issues related to the contribution of pharmacokinetics to susceptibility from occupational exposure to pharmaceutical compounds.
Pharmacological Reviews | 1973
Sydney Spector; Barry A. Berkowitz; Edward J. Flynn; Bernard Peskar
Journal of Pharmacology and Experimental Therapeutics | 1972
Edward J. Flynn; Sydney Spector
Alcohol and Alcoholism | 1996
Gina M. Pastino; Lester G. Sultatos; Edward J. Flynn