Abstract
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 (AUC0–24h) 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.
Highlights
Flupirtine (ethyl-N-[2-amino-6-(4-fluoro-phenylmethylamino) pyridin-3-yl] carbamate), an aminopyridine, is a centrally acting nonopiate analgesic that was first approved in Europe in 1984 and is marketed in India, China, and Brazil for treating acute and chronic pain in patients
Flupirtine shifts the gating of γ-aminobutyric acid (GABA) type-A receptors to a lower GABA concentration [4,5,10]
More recent studies suggest that flupirtine is a highly effective treatment for neonatal seizures in global hypoxia, hypoxic–ischemic encephalopathy (HIE), flurothyl, and kainic acid animal models and is more efficacious than the current first-line anticonvulsant drugs [14,15,16]
Summary
Flupirtine (ethyl-N-[2-amino-6-(4-fluoro-phenylmethylamino) pyridin-3-yl] carbamate), an aminopyridine, is a centrally acting nonopiate analgesic that was first approved in Europe in 1984 and is marketed in India, China, and Brazil for treating acute and chronic pain in patients. It is effective against pain involving the musculoskeletal system, tension headache, tumor pain, pain associated with dysmenorrhea, and pain following traumatic/orthopedic surgery and injuries [1,2,3]. Flupirtine acts primarily by opening KCNQ-type potassium (K+) channels during the early depolarization phase, thereby increasing the threshold for generating a neuronal action potential [4,5]. There is insufficient literature concerning the metabolism and distribution of flupirtine in various tissues after systemic administration in neonates
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