TY - JOUR
T1 - Pharmacokinetics of glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase and their blood glutamate-lowering activity in naïve rats
AU - Boyko, Matthew
AU - Stepensky, David
AU - Gruenbaum, Benjamin F.
AU - Gruenbaum, Shaun E.
AU - Melamed, Israel
AU - Ohayon, Sharon
AU - Glazer, Michael
AU - Shapira, Yoram
AU - Zlotnik, Alexander
N1 - Funding Information:
Acknowledgments The authors gratefully acknowledge Valeria Frishman (laboratory assistant at the Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev) for her outstanding help with the biochemical analysis. The help of Dr. Shira Ovadia (Director of Animal Resources Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev) is also gratefully acknowledged. We want to thank Dr. A. Alir and the staff of the Critical Care Unit, Soroka Medical Center, for their support and helpful discussions. This work was supported in part by grants to AZ from European Society of Anesthesiologists.
PY - 2012/10/1
Y1 - 2012/10/1
N2 - Traumatic brain injury (TBI) and stroke lead to elevated levels of glutamate in the brain that negatively affect the neurological outcomes in both animals and humans. Intravenous administration of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) enzymes can be used to lower the blood glutamate levels and to improve the neurological outcome following TBI and stroke. The objective of this study was to analyze the pharmacokinetics and to determine the glutamate-lowering effects of GOT and GPT enzymes in naïve rats. We determined the time course of serum GOT, GPT, and glutamate levels following a single intravenous administration of two different doses of each one of the studied enzymes. Forty-six male rats were randomly assigned into one of 5 treatment groups: saline (control), human GOT at dose 0.03 and 0.06 mg/kg and porcine GPT at dose 0.6 and 1.2 mg/kg. Blood samples were collected at baseline, 5 min, and 2, 4, 8, 12, and 24 h after the drug injection and GOT, GPT and glutamate levels were determined. The pharmacokinetics of both GOT and GPT followed one-compartment model, and both enzymes exhibited substantial glutamate-lowering effects following intravenous administration. Analysis of the pharmacokinetic data indicated that both enzymes were distributed predominantly in the blood (central circulation) and did not permeate to the peripheral organs and tissues. Several-hour delay was present between the time course of the enzyme levels and the glutamate-lowering effects (leading to clock-wise hysteresis on concentration-effect curves), apparently due to the time that is required to affect the pool of serum glutamate. We conclude that the interaction between the systemically-administered enzymes (GOT and GPT) and the glutamate takes place in the central circulation. Thus, glutamate-lowering effects of GOT and GPT apparently lead to redistribution of the excess glutamate from the brain's extracellular fluid into the blood and can reduce secondary brain injury due to glutamate neurotoxicity. The outcomes of this study regarding the pharmacokinetic and pharmacodynamic properties of the GOT and GPT enzymes will be subsequently verified in clinical studies that can lead to design of effective neuroprotective treatment strategies in patients with traumatic brain diseases and stroke.
AB - Traumatic brain injury (TBI) and stroke lead to elevated levels of glutamate in the brain that negatively affect the neurological outcomes in both animals and humans. Intravenous administration of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) enzymes can be used to lower the blood glutamate levels and to improve the neurological outcome following TBI and stroke. The objective of this study was to analyze the pharmacokinetics and to determine the glutamate-lowering effects of GOT and GPT enzymes in naïve rats. We determined the time course of serum GOT, GPT, and glutamate levels following a single intravenous administration of two different doses of each one of the studied enzymes. Forty-six male rats were randomly assigned into one of 5 treatment groups: saline (control), human GOT at dose 0.03 and 0.06 mg/kg and porcine GPT at dose 0.6 and 1.2 mg/kg. Blood samples were collected at baseline, 5 min, and 2, 4, 8, 12, and 24 h after the drug injection and GOT, GPT and glutamate levels were determined. The pharmacokinetics of both GOT and GPT followed one-compartment model, and both enzymes exhibited substantial glutamate-lowering effects following intravenous administration. Analysis of the pharmacokinetic data indicated that both enzymes were distributed predominantly in the blood (central circulation) and did not permeate to the peripheral organs and tissues. Several-hour delay was present between the time course of the enzyme levels and the glutamate-lowering effects (leading to clock-wise hysteresis on concentration-effect curves), apparently due to the time that is required to affect the pool of serum glutamate. We conclude that the interaction between the systemically-administered enzymes (GOT and GPT) and the glutamate takes place in the central circulation. Thus, glutamate-lowering effects of GOT and GPT apparently lead to redistribution of the excess glutamate from the brain's extracellular fluid into the blood and can reduce secondary brain injury due to glutamate neurotoxicity. The outcomes of this study regarding the pharmacokinetic and pharmacodynamic properties of the GOT and GPT enzymes will be subsequently verified in clinical studies that can lead to design of effective neuroprotective treatment strategies in patients with traumatic brain diseases and stroke.
KW - Glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase enzymes
KW - Neuroprotective activity in traumatic brain injury and stroke
KW - Pharmacokinetics and glutamate-lowering activity
UR - http://www.scopus.com/inward/record.url?scp=84866736057&partnerID=8YFLogxK
U2 - 10.1007/s11064-012-0843-9
DO - 10.1007/s11064-012-0843-9
M3 - Article
AN - SCOPUS:84866736057
SN - 0364-3190
VL - 37
SP - 2198
EP - 2205
JO - Neurochemical Research
JF - Neurochemical Research
IS - 10
ER -
