Back to Search
Start Over
Pharmacokinetics, Mass Balance, Excretion, and Tissue Distribution of Plasmalogen Precursor PPI-1011.
- Source :
-
Frontiers in cell and developmental biology [Front Cell Dev Biol] 2022 Apr 25; Vol. 10, pp. 867138. Date of Electronic Publication: 2022 Apr 25 (Print Publication: 2022). - Publication Year :
- 2022
-
Abstract
- PPI-1011 is a synthetic plasmalogen precursor in development as a treatment for multiple plasmalogen-deficiency disorders. Previous work has demonstrated the ability of PPI-1011 to augment plasmalogens and its effects in vitro and in vivo , however, the precise uptake and distribution across tissues in vivo has not been investigated. The purpose of this study was to evaluate the pharmacokinetics, mass balance, and excretion of [ <superscript>14</superscript> C]PPI-1011 following a single oral administration at 100 mg/kg in Sprague-Dawley rats. Further tissue distribution was examined using quantitative whole-body autoradiography after both single and repeat daily doses at 100 mg/kg/day. Non-compartmental analysis showed that following a single dose, PPI-1011 exhibited peak levels between 6 and 12 h but also a long half-life with mean t <subscript>1/2</subscript> of 40 h. Mass balance showed that over 50% of the compound-associated radioactivity was absorbed by the body, while approximately 40% was excreted in the feces, 2.5% in the urine, and 10% in expired air within the first 24 h. Quantitative whole-body autoradiography following a single dose showed uptake to nearly all tissues, with the greatest initial uptake in the intestines, liver, and adipose tissue, which decreased time-dependently throughout 168 h post-dose. Following 15 consecutive daily doses, uptake was significantly higher across the entire body at 24 h compared to single dose and remained high out to 96 h where 75% of the initially-absorbed compound-associated radioactivity was still present. The adipose tissue remained particularly high, suggesting a possible reserve of either plasmalogens or alkyl diacylglycerols that the body can pull from for plasmalogen biosynthesis. Uptake to the brain was also definitively confirmed, proving PPI-1011's ability to cross the blood-brain barrier. In conclusion, our results suggest that oral administration of PPI-1011 results in high uptake across the body, and that repeated dosing over time represents a viable therapeutic strategy for treating plasmalogen deficiencies.<br />Competing Interests: TS, KK, and SR are paid employees of Med-Life Discoveries LP.<br /> (Copyright © 2022 Smith, Knudsen and Ritchie.)
Details
- Language :
- English
- ISSN :
- 2296-634X
- Volume :
- 10
- Database :
- MEDLINE
- Journal :
- Frontiers in cell and developmental biology
- Publication Type :
- Academic Journal
- Accession number :
- 35547803
- Full Text :
- https://doi.org/10.3389/fcell.2022.867138