Limits...
Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

Rais R, Wozniak K, Wu Y, Niwa M, Stathis M, Alt J, Giroux M, Sawa A, Rojas C, Slusher BS - PLoS ONE (2015)

Bottom Line: Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration.Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas.Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement.

View Article: PubMed Central - PubMed

Affiliation: Brain Science Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.

No MeSH data available.


Related in: MedlinePlus

Brain tissue to plasma (B/P) ratio of 2-PMPA in different brain regions.B/P ratio was calculated based on area under the curve (AUC0-t) following 30 mg/kg i.n. or i.p. administration.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494705&req=5

pone.0131861.g004: Brain tissue to plasma (B/P) ratio of 2-PMPA in different brain regions.B/P ratio was calculated based on area under the curve (AUC0-t) following 30 mg/kg i.n. or i.p. administration.

Mentions: Pharmacokinetic studies of 30 mg/kg 2-PMPA in rat plasma and brain tissues following i.n. and i.p. administration were conducted and compared. Similar to what we have previously demonstrated [45], i.p. administered 2-PMPA showed rapid absorption in plasma with peak plasma concentration (Cmax) of 49.5 μg/mL observed at the first time point of 0.167 h. The AUC0-t achieved for plasma was 50.3 h*μg/mL and the elimination t1/2 value was 0.99 h depicting rapid elimination. The apparent volume of distribution was low (0.82 L/kg) and the apparent clearance was rapid (9.71 mL/min/kg). The AUC0-t achieved for olfactory bulb, cortex and cerebellum were 1.15 h*μg/g, 0.84 h*μg/g, and 0.80 h*μg/g respectively (Fig 3A). The brain tissue to plasma ratios based on AUCs (AUC0-t,brain/AUC0-t,plasma) was less than 0.02 for olfactory bulb, cortex, and cerebellum (Fig 4).


Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

Rais R, Wozniak K, Wu Y, Niwa M, Stathis M, Alt J, Giroux M, Sawa A, Rojas C, Slusher BS - PLoS ONE (2015)

Brain tissue to plasma (B/P) ratio of 2-PMPA in different brain regions.B/P ratio was calculated based on area under the curve (AUC0-t) following 30 mg/kg i.n. or i.p. administration.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494705&req=5

pone.0131861.g004: Brain tissue to plasma (B/P) ratio of 2-PMPA in different brain regions.B/P ratio was calculated based on area under the curve (AUC0-t) following 30 mg/kg i.n. or i.p. administration.
Mentions: Pharmacokinetic studies of 30 mg/kg 2-PMPA in rat plasma and brain tissues following i.n. and i.p. administration were conducted and compared. Similar to what we have previously demonstrated [45], i.p. administered 2-PMPA showed rapid absorption in plasma with peak plasma concentration (Cmax) of 49.5 μg/mL observed at the first time point of 0.167 h. The AUC0-t achieved for plasma was 50.3 h*μg/mL and the elimination t1/2 value was 0.99 h depicting rapid elimination. The apparent volume of distribution was low (0.82 L/kg) and the apparent clearance was rapid (9.71 mL/min/kg). The AUC0-t achieved for olfactory bulb, cortex and cerebellum were 1.15 h*μg/g, 0.84 h*μg/g, and 0.80 h*μg/g respectively (Fig 3A). The brain tissue to plasma ratios based on AUCs (AUC0-t,brain/AUC0-t,plasma) was less than 0.02 for olfactory bulb, cortex, and cerebellum (Fig 4).

Bottom Line: Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration.Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas.Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement.

View Article: PubMed Central - PubMed

Affiliation: Brain Science Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.

No MeSH data available.


Related in: MedlinePlus