The prediction of plasma and brain levels of 2,3,5,6-tetramethylpyrazine following transdermal application

Abstract

INTRODUCTIONThe biologically active ingredient 2,3,5,6-tetramethylpyrazine (TMP, structure shown in Figure 1), originally isolated from Ligusticum wallichii Franch in 1957, has been used routinely in China for the treatment of stroke and angina pectoris. 1,2 It was recognized as a candidate for a cognitive enhancer, as it showed significant actions such as improving brain microcirculation and blood viscosity.3 It was reported recently that following an intravenous administration of 2, 5, or 10 mg/kg to rats, TMP penetrated through the blood-brain barrier within 10 minutes. The concentrations of TMP in various regions of the brain (cerebral cortex, brainstem, striatum, hippocampus, cerebellum, and midbrain) were not significant at 15 minutes. 4 Analysis of the relationship between brain and blood levels yields a progressive brain/blood ratio suggesting appreciable blood-brain barrier penetrability of TMP. 5The purpose of this study was to construct a pharmacokinetic (PK) model and to determine PK parameters of 2,3,5,6-tetramethylpyrazine (TMP) after application of TMP transdermal delivery system. Data were obtained in Sprague-Dawley (SD) rats following a single dose of TMP transdermal delivery system. Blood samples were obtained at 0, 0.25, 0.5, 1, 2, 4, 6, 16, and 24 hours after the transdermal application. In the brain level study, 18 SD rats were divided into 6 groups. Three SD rats before and after transdermal application were culled and sacrificed at each of the following time intervals: 2, 4, 6, 16, and 24 hours after the TMP-TTS application. TMP concentrations in plasma and brain tissues were determined using high performance liquid chromatography and data were fitted using a zero-order absorption and a firstorder-elimination 3-compartment PK model. Fitted parameters included 2 volumes of distribution (V 1 , V 2 ) and 2 elimination rate constants (k 10 , k 20 ). The elimination half-life for TMP in plasma and brain was 26.5 and 31.2 minutes, respectively. The proposed PK model fit observed concentrations of TMP very well. This model is useful for predicting drug concentrations in plasma and brain and for assisting in the development of transdermal systems.Oral administration of TMP is known to exhibit extensive first-pass metabolism, low oral bioavailability (10%-30%), and short biological half-life of 0.5 to 2 hours.6,7 TMP can be given orally 100 mg 3 times daily. To maintain therapeutic blood levels for long periods, intravenous infusion is needed in the treatment; for instance, TMP hydrochloride injection (40 mg/2 mL) or TMP phosphate injection (50 mg/2 mL) is diluted with 250 to 500 mL of isotonic saline or glucose solution and intravenously infused for 4 to 6 hours. 8 For maintenance therapy, controlled release through an alternative route may be more meaningful, since frequent oral dosing and 4 to 6 hours of intravenous infusion may lead to noncompliance.KEYWORDS: tetramethylpyrazine, percutaneous absorption, transdermal drug delivery system, in vitro/in vivo, pharmacokinetic model It is ve...

Tetramethylpyrazine inhibits production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through blockade of MAPK and PI3K/Akt signaling pathways, and suppression of intracellular reactive oxygen species

“…Because of extensive fist-pass metabolism, TMP is recommended to be given intravenously instead of oral administration in the treatment (Qi et al, 2002). Considering the dose range of TMP (1-10 mg/kg) used in in vivo studies, efficient permeability to blood-brain barrier, and comparable protein binding in serumsupplemented media and plasm (Liang et al, 1999;Tan, 2009;Tsai and Liang, 2001), we consider that the concentrations of TMP used for cell culture experiments might be relevant to plasma and tissue levels achievable clinically.…”

Simple High-Performance Liquid Chromatographic Method for the Determination of Tetramethylpyrazine Phosphate in Very Small Volumes of Dog Plasma: Application to a Pharmacokinetic Study

“…Several studies on the determination of tetramethylpyrazine (TMP) in biological fluids have been performed using gas chromatography-mass spectrometry (MS) (5)(6)(7)(8) or liquid chromatography (LC)-MS (9), but it requires MS equipment that may not be available in many laboratories. Some workers have also employed the high-performance liquid chromatography (HPLC) method with UV detection for the assay of TMP (10)(11)(12). Most of these methods (11,12) require complicated sample preparation procedures involving basification of plasma sample, extraction, acidification, preconcentration, and reconstitution of the analytes.…”

“…Some workers have also employed the high-performance liquid chromatography (HPLC) method with UV detection for the assay of TMP (10)(11)(12). Most of these methods (11,12) require complicated sample preparation procedures involving basification of plasma sample, extraction, acidification, preconcentration, and reconstitution of the analytes. These procedures are rather time-consuming and are more complex than the procedure described in this paper.…”

Development of a reservoir-type transdermal delivery system containing eucalyptus oil for tetramethylpyrazine

“…Therefore, the use of TMP free base may be more effective for achieving a therapeutic plasma level than its salts. Various TDSs for TMP such as microemulsions (Zhao et al, 2011), ethosomes (Liu et al, 2011a,b) and matrix-type (Qiu et al, 2006) or reservoir-type patches (Qi et al, 2002(Qi et al, , 2003b have been fabricated. Their improvement of permeation across animal skin has been observed in vitro, while prolonged and sustained plasma drug levels have been demonstrated in rats or rabbits in vivo.…”