| Venlafaxine is a structurally novel phenethylamine bicyclic antidepressant for oral administration, which inhibits the reuptake of presynaptic serotonin and noradrenaline. In the massive use in clinic, the treatment dosages are quite different, the effective dosages of venlafaxine range from 75-450mg/d and the effect has no obvious relation with the venlafaxine concentration in blood. In order to get to know the pharmacokinetic and the ability to pass through BBB, the reaserch was conducted in these two aspects, so as to know the feature of it and to provide theoretical proof in the application of it..A high performance liquid chromatography (HPLC) method was established for the determination of venlafaxine. Both the intra-day and the inter-day precision of the method were less than 10%, a linear plot of plasma venlafaxine versus peak area was within the range of 0.25-32μg·ml-1, and a linear range of brain tissue venlafaxine was 0.05-6.40μg·g-1. The average recovery of venlafaxine in plasma was 89.4%, and the lowest concentration of quantification for venlafaxine in plasma was 0.25μg·ml-1. The average recovery in brain tissue was 93.3%, and the lowest concentration of quantification for venlafaxine in brain tissue was 12.5μg·g-1. Plasma sample could keep stability at room temperature for 1d and at 4℃to -20℃for two weeks.Brain tissue sample was fitted to be stored stability at -20℃for two weeks.The concentration-time profile in rats was best fitted to two-compartment model after a single administrated intravenous of 10 mg·kg-1 venlafaxine. The main TK parameters : t1/2αwas 5.46±4.33 min, Vb was 2.4±0.29L·kg-1, t1/2βwas 65.18±12.88 min, and CLs was 0.026±0.005 L·kg-1·min-1. The results demonstrated that venlafaxine distributed widely and eliminated rapidly after intravenous administration in rats. The concentration of venlafaxine in brain tissue was higher than that in plasma.Venlafaxine had selectivity in the distribution in brain tissue and passed through BBB easily without obvious absorption process.The plasma concentration-time profiles in rats were singlet or bimodal curves after single intragastric administration with 50mg·kg-1,100mg·kg-1,200mg·kg-1 venlafaxine. The main TK parameters: Tmax1 was 10～30 min,Tmax2 was 60～120 min,t1/2ke was 20～317 min,and F was 1.8%～42.4%. AUC and F of venlafaxine did not increase proportionally with the dosages. The plasma concentration-time profiles were greatly different after drenching venlafaxine of identical dosage, which was greatly conformed to the phenomenon in clinical therapy.The absorption of venlafaxine slowed down at the first part and enhanced at the second part after a single intragastric administration with venlafaxin and zinc chloride. It means that Zn2+ may inhibit the absorption of venlafaxine in the first part and promote it in the second part. The increase of AUC and F of venlafaxine suggests that Zn2+ may promote absorption of venlafaxine, and thereby Zn2+ may enhance antidepress effect of venlafaxine.By adopting situ bilateral brain perfusion technique and multiple-time uptake data analysis method, the dynamics feature of venlafaxin transporting across blood-brain barrier was studied on. Venlafaxine can get across blood-brain barrier into brain parenchyma at different perfusion concentrations. Brain unidirectional transfer constant(Kin) values for venlafaxine diminished with the increase of perfusion concentration, Kin reached as high as to 1.13 mL·min-1·g-1 ,which was about 70% of the perfusion speed. But Kin decreased to 0.53 mL·min-1·g-1 and 0.31 mL·min-1·g-1 respectively when perfusion speed was raised to 5 times and 25 times, which were 33% and 19% of perfusion speed.The initial distribution volume(Vi) values for venlafaxine of distinct concentrations were -4.7,-1.08,-0.37 mg·g-1 in order. The absolute value of them were 4.7, 1.1, and 0.4 respectively. It shows that brain tissue may have an effect to attract the concentration of venlafaxine. This effectdecreases with the increase of the dosage.Th result shows that the transport of venlafaxine across blood-brain barrier fits to the model of passive diffusion in a membrane-limited rate. |
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