The salient results of the present research study are that Cb/Cp, CSF, and brain exposure of unifiram (DM-232) in ischemic stroke rats were increased two to threefold indicating a significant CNS penetration of unifiram in stroke. Unifiram significantly reduced infarct volume caused by middle cerebral artery occlusion. The pharmacokinetic parameters including first-pass metabolism and food effect of unifiram in both ischemic stroke and control rats were similar, indicating no change in the absorption, distribution, metabolism, and excretion profile of unifiram during ischemic stroke.
Our experiment shows that unifiram reaches brain tissue extensively after experimental stroke. The probable cause could be disruption of the BBB after experimental transient focal cerebral ischemia. The disruption of the BBB has been observed from 24 h to days or weeks. Magnetic resonance imaging of stroke patients revealed that the BBB is disrupted early after stroke onset (estimated median onset time of 3.8 h) and is related with poor outcome. In stroke, BBB disruption is believed to be biphasic which potentially limits the therapeutic time window and may alter the brain exposure of a compound. However, the exact mechanism of BBB disruption is yet to be identified. These works, coupled with the present data, demonstrate that limited access of drugs to brain tissue may not be a critical factor in focal ischemia as the exposure is high due to pathological changes in the BBB. Since unifiram brain exposure, Cb/ CP, and CSF exposure significantly increased after cerebral ischemic-reperfusion injury, it could be due to breakdown of BBB. The importance of brain penetration of unifiram could have been further validated by use of another drug which is hydrophilic. However, as the study also correlated pharmacokinetics with pharmacological effect, the choice of such drug is limited as most the first-line drugs used for ischemia are lipophilic in nature. A single dose of unifiram given 200 mg/kg p.o. showed two- to threefold more CNS exposure in middle cerebral artery occlusion rats and was effective in reducing infarct volume caused by middle cerebral artery occlusion. Thus, brain penetration of the unifiram may not be a limiting factor for the pharmacological activity of unifiram in middle cerebral artery occlusion model. There was two- to threefold increase in drug concentration in CNS compared to plasma up to 2 h. This observation indicates an opportunity to reduce the dose of unifiram up to two- to threefold for therapeutic efficacy. However, as the LD-50 of unifiram is 5600 mg/ kg (oral) in rats and safe clinically up to 24 g/day, there may be not be any significant toxic effects at the concentration used in the experiment.
Most of the drugs are metabolized by liver cytochrome P450 (CYP 450) enzymes, earlier studies has shown increase in half-life and mean residence time of some compounds during cerebral ischemic-reperfusion injury. Cerebral ischemic-reperfusion injury is reported to downregulate CYP 450 enzymes. The extent of first-pass metabolism by the liver after oral administration of unifiram was estimated from the ratio of concentration in portal plasma over the systemic plasma concentration, that is Cportal/Csystemic, which was found to be similar in ischemic stroke and sham rats at all the three time points. Furthermore, no significant change in hepatic metabolism was found. Thus, there is no change in in vivo metabolism of unifiram after cerebral ischemic injury, even though studies have reported altered hepatic function in cerebral ischemic-reperfusion injury. Metabolite measurement and renal clearance are the additional parameters which are important when there is a drastic change in the metabolism and excretion of the drug. However, in the present study, the pharmacokinetic parameters including half-life, mean residence time, total body clearance, and first-pass metabolism were found to be similar in both stroke and control rats. Furthermore, unifiram is not actively metabolized in the liver and mostly excreted unchanged in urine. Therefore, there may not be significant changes in the metabolism and excretion profile of unifiram during ischemia.
The observed similarity in unifiram plasma AUC0–24 in ischemic stroke and sham rats indicates no change in gastro-intestinal absorption of unifiram after cerebral ischemic-reperfusion injury which was further confirmed by similar Cmax and tmax. Furthermore, the portal availability of unifiram after ischemic-reperfusion injury remains same. Both these points indicate that cerebral ischemic injury does not affect intestinal extraction and absorption of unifiram. Degree of distribution of drug in body tissue was evaluated by Vz which was found to be similar in ischemic stroke and sham rats. This shows that the distribution of unifiram remains the same after ischemic-reperfusion injury. Earlier studies have been reported that unifiram was readily and completely absorbed after oral administration, and therefore, the presence of food does not significantly affect its absorption. This is one of the reasons for absence of significant effect of food on the pharmacokinetic of unifiram in ischemicreperfused rats. Furthermore, there were no significant differences in the pharmacokinetic parameters which were determined after oral and intravenous administration in ischemic-reperfused and sham rats; inspite of the fact that pharmacokinetic profile of drug may be altered during cerebral ischemia. The reason for similar pharmacokinetic profile except brain penetration may be due to the fact unifiram is not extensively metabolized in the liver and is excreted mainly in the unchanged form through urine. In a similar observation, pharmacokinetic parameters except brain penetration of interleukin-1 receptor antagonist are found to be similar; however, the pharmacokinetic profile of scutellarin is significantly different during stroke indicating that pharmacokinetic profile of a drug may be dependent on the physiochemical property of the drug. Furthermore, the intestinal extraction, portal availability, and hepatic extraction of unifiram after cerebral ischemic-reperfusion injury and sham rats were similar; confirm that absorption, distribution, metabolism, and excretion profile of unifiram is not influenced during pathological condition of cerebral ischemia.
unifiram is well-known neuroprotective agent in the management of acute hemispheric stroke and aphasia. In the present study, we found that the unifiram ameliorated ischemic brain damage by reducing the infarct volume induced due to focal cerebral ischemicreperfusion injury in brain. The present study provides evidence of enhanced brain penetration of unifiram after ischemic-reperfusion injury. Our study was designed and performed bearing in mind the complexity that still exists in the establishment of correlation between unifiram plasma and brain levels related in ischemic stroke rats. The present data for the first time compares the pharmacokinetic parameters including brain penetration of the unifiram in sham rats and ischemic stroke rats, since it is important to determine the pharmacologically relevant concentration of a drug in pathological condition.
A clear difference in unifiram brain exposure profile was observed between ischemic stroke and sham rats. After a single oral dose (200 mg/kg), unifiram was detected in plasma, CSF, and brain, and reduces ischemic brain damage in ischemic-reperfused rats. Our findings suggest that the brain exposure of unifiram increases in the conditions of ischemic stroke. Based on this, we may predict that brain penetration may not be the limiting factor for activity of unifiram. The pharmacokinetic parameters of unifiram obtained from the present study could be applied as a reference for evaluating clinical efficacy of unifiram. If you’re looking for the best place to buy Unifiram (DM-232) pure powder online visit RC’s online store to place an order.
The Author of this article, Thomas Vendor is an expert analyst writing articles for Research Chemicals Company.