Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers

Abstract

L-3-n-butylphthalide (L-NBP) is a naturally occurring antioxidant, which can be used for the treatment of acute ischemic stroke and vascular dementia. This study evaluated the safety, tolerability and pharmacokinetics of L-NBP tablets in healthy Chinese volunteers. This was a single-center, randomized, double-blind, placebo-controlled, single-and multiple-dose study. Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12). Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of L-NBP were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration; AEs in this study occurred less frequently and more mildly than AEs listed for the DL-NBP soft capsule. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, C max was reached at about 1 h, and the mean t 1/2 was approximately 13.76 h. Area under curve (AUC) and C max increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, the steady-state was reached within 3 days with slight accumulation. In summary, the L-NBP tablet was well tolerated in healthy Chinese subjects. Slight accumulation appeared after repeated doses.Uniterms: L-3-n-butylphthalide/tablets/safety. L-3-n-butylphthalide/tablets/tolerability. L-3-nbutylphthalide/tablets/pharmacokinetics. Natural antioxidant.L-3-n-butilftalida (L-NMP) é um antioxidante natural, que pode ser utilizado para o tratamento do acidente isquêmico agudo e demência vascular. Este estudo avaliou segurança, tolerância e farmacocinética de comprimidos de L-NBP em chineses voluntários sadios. Este foi um estudo monocêntrico, randomizado, duplo cego, com controle por placebo e doses única e múltipla. Os indivíduos receberam dose única de comprimido de L-NBP de 80, 160, 320 ou 480 mg (n=40) e doses múltiplas de 160 mg duas vezes ao dia, por sete dias (n=12). Amostras de plasma foram analisadas com LC-MS/MS. Os parâmetros farmacocinéticos do L-NBP foram calculados utilizando análise não compartimental, com o programa WinNonlin. A análise estatística foi realizada utilizando-se o programa SPSS. Todos os eventos adversos (EAs) foram moderados e de duração limitada. EAs nesse estudo ocorreram menos frequentemente e mais moderadamente do que os EAs relacionados para cápsulas moles de DL-NBP. Não se observaram eventos adversos graves (EAG), morte ou abandono do estudo. Com dose única, atingiu-se o C max em cerca de 1 hora e o t 1/2 médio foi de, aproximadamente, 13,76 h. A área sob a curva (ASC) e o C max aumentaram com o aumento da dose, mas não se observou proporcionalidade na faixa acima de 160 a 480 mg. No estudo de dose múltipla, o equilíbrio foi alcançado em três dias, com pequeno acúmulo. Em resumo, o comprimido de L-NMP foi bem tolerado em indivíduos chineses sau...

A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives

“…Extensive experimental and clinical studies have furthermore confirmed those properties leading to the approval and marketing of dl-NBP as an anti-ischemic drug in China since 2002. Several studies focused on the human metabolism and pharmacokinetics of NBP showed that NBP is safe for human usage [4] and that it essentially undergoes oxidation by cytochrome P450 (P450) after oral administration, resulting in 23 identified metabolites, among which 10-keto-NBP (M2), 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2), and NBP-11-oic acid (M5-2) are considered as major metabolites [5, 6]. Those studies also established that hydroxylation of the n-butyl side chain and C-3 constitutes the main metabolic route and that urine is the main excretion pathway of dl-NBP metabolites [6].…”

Application and prospects of butylphthalide for the treatment of neurologic diseases

“…[27] As stated, in 2002, NBP was approved by the China Food and Drug Administration for clinical trials for the treatment of cerebral ischemia. [28] According to the results of a recent clinical trial, the efficiency of NBP for the treatment of ischemic cerebrovascular disease is as high as 74.7%, with a low incidence of adverse reactions. [29] Further, a series of studies has shown that NBP is safe for clinical treatment.…”

Microbial Metabolites of 3-n-butylphthalide as Monoamine Oxidase A Inhibitors

“…The compound 3- n -butylphthalide is a biologically active lactone found in plants from the celery family [ 11 , 12 ]. Originally an ingredient in traditional Chinese medicine, it was accepted in China as a drug for cerebral ischemic stroke that improves the neurological function of the patients [ 13 , 14 , 15 ]. The compound restores microcirculation and protects the mitochondria.…”