Smith Tara, Knudsen Kaeli J, Ritchie Shawn A
Med-Life Discoveries LP, Saskatoon, SK, Canada.
Front Cell Dev Biol. 2022 Apr 25;10:867138. doi: 10.3389/fcell.2022.867138. eCollection 2022.
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 and , however, the precise uptake and distribution across tissues has not been investigated. The purpose of this study was to evaluate the pharmacokinetics, mass balance, and excretion of [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 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.
PPI - 1011是一种正在研发的合成缩醛磷脂前体，用于治疗多种缩醛磷脂缺乏症。先前的研究表明PPI - 1011具有增加缩醛磷脂的能力及其效果，然而，其在各组织中的精确摄取和分布尚未得到研究。本研究的目的是评估在100mg/kg单次口服给药后，[C]PPI - 1011在斯普拉格 - 道利大鼠体内的药代动力学、质量平衡和排泄情况。在100mg/kg/天的单次和重复每日剂量后，使用定量全身放射自显影术进一步检查组织分布。非房室分析表明，单次给药后，PPI - 1011在6至12小时之间出现峰值水平，但半衰期也很长，平均t为40小时。质量平衡表明，超过50%的化合物相关放射性被身体吸收，而在最初的24小时内，约40%通过粪便排出，2.5%通过尿液排出，10%通过呼出气体排出。单次给药后的定量全身放射自显影显示几乎所有组织都有摄取，最初在肠道、肝脏和脂肪组织中的摄取量最大，在给药后168小时内随时间下降。连续15天每日给药后，与单次给药相比，24小时时全身摄取量显著更高，并在96小时时仍保持较高水平，此时最初吸收的化合物相关放射性的75%仍然存在。脂肪组织中的摄取量仍然特别高，这表明身体可能储备了缩醛磷脂或烷基二酰甘油，可用于缩醛磷脂的生物合成。对大脑的摄取也得到了明确证实，证明了PPI - 1011穿过血脑屏障的能力。总之，我们的结果表明，口服PPI - 1011会导致全身摄取量高，并且随着时间的推移重复给药是治疗缩醛磷脂缺乏症的一种可行治疗策略。
