Patil Madhoosudan A, Matter Brock A, Raol Yogendra H, Bourne David W A, Kelley Ryan A, Kompella Uday B
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pediatrics, Division of Neurology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Pharmaceutics. 2018 Dec 16;10(4):281. doi: 10.3390/pharmaceutics10040281.
Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223.
氟吡汀是一种非阿片类镇痛药，对治疗新生儿惊厥有效。然而，其在新生哺乳动物体内的脑内递送情况和药代动力学尚不清楚。本研究的目的是确定氟吡汀在新生动物各组织（如脑）中的药代动力学及其活性代谢物D - 13223的形成情况。出生后第7天，给幼鼠腹腔注射25 mg/kg氟吡汀。给药后长达24小时收集肝脏、心脏、肾脏、肺、脾脏、视网膜、血清以及脑区海马体、皮层和其余脑区（不含小脑）。开发了一种液相色谱 - 串联质谱法（LC - MS/MS）来定量氟吡汀和D - 13223。氟吡汀被递送至所有评估的组织，肝脏中浓度 - 时间曲线下面积（AUC）最高（488 µg·h/g组织），脾脏中最低（82 µg·h/g组织）。给药后1小时内氟吡汀到达脑内，包括海马体和皮层，并在24小时时仍有残留。各脑区氟吡汀的AUC约为195 µg·h/g组织。氟吡汀在各组织中的半衰期为3.1至5.2小时。D - 13223在体内形成，并在所有评估组织中检测到，肝脏中的浓度最高。将分离的新生大鼠肝脏、心脏、肾脏、肺、脾脏、全眼、血清或全脑与氟吡汀在37℃孵育3小时，除血清外，所有组织均形成了D - 13223。D - 13223在分离的肝脏组织中形成量最高。基于分离组织摄取的组织分配系数与体内组织 - 血清药物暴露比相关性良好。因此，氟吡汀可从全身途径到达新生大鼠的靶脑组织，且脑组织可形成活性代谢物D - 13223。
