Pharmacokinetics of Glutamate–Oxaloacetate Transaminase and Glutamate–Pyruvate Transaminase and Their Blood Glutamate-Lowering Activity in Naïve Rats

Abstract

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.

A new post-intoxication treatment of paraoxon and parathion poisonings using an evolved PON1 variant and recombinant GOT1

“…7). The results fit well to a bi-exponential curve (R ¼ 0.997) and are in contrast to the conclusion of Boyko et al which attributed a single exponential decay kinetics for rGOT1 in rats [44]. A possible explanation for this discrepancy is that during their pharmacokinetic study, Boyko et al had begun samplings only 3 h post injection and thus missed the first rapid-equilibration phase of GOT1.…”

“…The half life time of rGOT1 in rat blood was previously reported to be 3 h [44]. We examined the pharmacokinetics of the rGOT1 dose that was injected in our experiments by monitoring the time course of GOT activity in the plasma of naïve rats at different times (Fig.…”

Neuroprotective Effect of Oxaloacetate in a Focal Brain Ischemic Model in the Rat

“…The enzymatic activity of GOT has been reported to be higher than that of GPT both in rats and in humans (Teichberg, 2011). Boyko et al (2012) first described the pharmacokinetic and pharmacodynamic properties of GOT and GPT. They found that these two enzymes are largely distributed in the central circulation and their interactions with Glu also take place there.…”

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“…GPT metabolizes glutamate in the peripheral blood, possibly reducing the risk of excitotoxicity [21,33]. In rats, GPT was proven to exert neuroprotective effects due to breakdown of glutamate in the peripheral blood [34,35]. D-dimer was the only biomarker significant in the group of the haemostatic biomarkers.…”