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...
