抗银屑病新药苯烯莫德大鼠药物动力学及其乳猪皮肤分布
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摘要
目的建立生物样品中苯烯莫德的高效液相色谱法(HPLC)测定方法并进行大鼠体内药物动力学、组织分布及乳猪皮肤分布的研究。方法大鼠皮下注射苯烯莫德后,于不同时间点眼眶静脉丛采血,乙酸乙酯提取大鼠血浆及组织中的苯烯莫德。乳猪涂抹苯烯莫德后,不同时间点于前腔静脉取血,取皮肤。HPLC测定生物样品中苯烯莫德的含量,DAS软件计算药物动力学参数。结果大鼠皮下注射3种剂量(3、9和27 mg/kg)苯烯莫德,体内血药浓度-时间曲线下面积(AUC)符合二室模型的动力学特征,按二室模型计算的t_(1/2α)分别为(0.65±0.27)、(0.78±0.13)和(0.53±0.26)h,t_(1/2β)分别为(3.40±0.88)、(3.80±0.62和(4.70±0.41)h,达峰浓度分别为(84.89±13.76)、(166.90±31.37)和(385.20±98.68)ng/ml,AUC0-t分别为(243.20±34.01)、(786.10±176.90)、(2 677.00±255.10)ng/ml·h。SD大鼠皮下注射苯烯莫德(9 mg/kg)后10 min,各脏器中即有分布,其中肝、肾、脾、胃、甲状腺、卵巢、胰腺、皮肤中含量较高。乳猪皮肤涂抹给药24 h后,皮肤中苯烯莫德药物含量达(104.17±13.36)μg/g,乳猪血药浓度低于最低定量浓度(5 ng/ml)。结论本方法快速、准确、简便,能够满足苯烯莫德药物动力学研究要求。苯烯莫德大鼠皮下注射给药后其进入体内血液循环的药量较少。乳猪皮肤涂抹给药后皮肤内药物含量较高,血浆浓度极低。
Objective To study the pharmacokinetics of benvitimod in rats and porklings through HPLC. Methods The rat blood samples were taken from orbital venous plexus at different time points after subcutaneous injection of benvitimod in rats. The ethyl acetate was used for the extraction of benvitimod from biological samples(plasma and tissue). After topical use of benvitimod for porklings, the anterior vena cava blood samples and the skin samples were taken at different time points. The concentrations of benvitimod in biological samples were measured by HPLC method and the pharmacokinetics parameters were calculated by DAS. Results The pharmacokinetics profiles of benvitimod were best described by two compartment model. The main plasma pharmacokinetics parameters of benvitimod following the subcutaneous injection administration of 3, 9, 27 mg/kg in rats were as follows: t_(1/2α) [(0.65±0.27),(0.78±0.13) and(0.53±0.26) h]; t_(1/2β) [(3.40±0.88),(3.80±0.62) and(4.70±0.41) h]; Cmax [(84.89±13.76),(166.90±31.37),(385.20±98.68) ng/ml]; AUC0-t [(243.20±34.01),(786.10±176.90),(2 677.00±255.10) ng/ml·h]. The distribution of benvitimod in rats, following the subcutaneous injection administration of 9 mg/kg showed that benvitimod was mostly accumulated in thyroid gland, skin, liver, kidney, spleen and stomach etc. In porklings, the concentration of bentivimod was(104.17±13.36) μg/g in skin after 24 h of topical application. There was only minimally present in the plasma levels, which was lower than the detection limit of quantitation(5 ng/ml).Conclusion The HPLC method for bentivimod determination of biological samples is sensitive, stable and rapid, which is successfully used for the pharmacokinetics study. The plasma concentration of bentivimod is low after subcutaneous injection in rats. After topical use of bentivimod in porklings, the skin concentration can achieve the effective level.
Objective To study the pharmacokinetics of benvitimod in rats and porklings through HPLC. Methods The rat blood samples were taken from orbital venous plexus at different time points after subcutaneous injection of benvitimod in rats. The ethyl acetate was used for the extraction of benvitimod from biological samples(plasma and tissue). After topical use of benvitimod for porklings, the anterior vena cava blood samples and the skin samples were taken at different time points. The concentrations of benvitimod in biological samples were measured by HPLC method and the pharmacokinetics parameters were calculated by DAS. Results The pharmacokinetics profiles of benvitimod were best described by two compartment model. The main plasma pharmacokinetics parameters of benvitimod following the subcutaneous injection administration of 3, 9, 27 mg/kg in rats were as follows: t_(1/2α) [(0.65±0.27),(0.78±0.13) and(0.53±0.26) h]; t_(1/2β) [(3.40±0.88),(3.80±0.62) and(4.70±0.41) h]; Cmax [(84.89±13.76),(166.90±31.37),(385.20±98.68) ng/ml]; AUC0-t [(243.20±34.01),(786.10±176.90),(2 677.00±255.10) ng/ml·h]. The distribution of benvitimod in rats, following the subcutaneous injection administration of 9 mg/kg showed that benvitimod was mostly accumulated in thyroid gland, skin, liver, kidney, spleen and stomach etc. In porklings, the concentration of bentivimod was(104.17±13.36) μg/g in skin after 24 h of topical application. There was only minimally present in the plasma levels, which was lower than the detection limit of quantitation(5 ng/ml).Conclusion The HPLC method for bentivimod determination of biological samples is sensitive, stable and rapid, which is successfully used for the pharmacokinetics study. The plasma concentration of bentivimod is low after subcutaneous injection in rats. After topical use of bentivimod in porklings, the skin concentration can achieve the effective level.
引文
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[2]Bourcier M,Papp KA,Gulliver WP.Long-term management of moderate to severe plaque psoriasis patients with etanercept:a case series[J].J Cutan Med Surg,2015,19(6):561-569.
[3]D'Amico F,Trovato C,Skarmoutsou E,et al.Effects of adalimumab,etanercept and ustekinumab on the expression of psoriasin(S100A7)in psoriatic skin[J].J Dermatol Sci,2015,80(1):38-44.
[4]Sugiura K,Endo K,Akasaka T,et al.Successful treatment with infliximab of sibling cases with generalized pustular psoriasis caused by deficiency of interleukin-36 receptor antagonist[J].J Eur Acad Dermatol Venereol,2015,29(10):2054-2056.
[5]Papp KA,Menter A,Strober B,et al.Efficacy and safety of tofacitinib,an oral Janus kinase inhibitor,in the treatment of psoriasis:a phase 2b randomized placebo-controlled doseranging study[J].Br J Dermatol,2012,167(3):668-677.
[6]Bachelez H,van de Kerkhof PC,Strohal R,et al.Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis:a phase 3 randomised non-inferiority trial[J].Lancet,2015,386(9993):552-561.
[7]陈明,钟杰敏,刘冠萍,等.银屑病治疗靶点及其药物研发进展[J].中国医院药学杂志,2015,35(9):846-850.
[8]马晓蕾,温广东,赵琰,等.苯烯莫德对人外周血单个核细胞增殖、凋亡作用及对T细胞NF-?B的调节[J].中国皮肤性病学杂志,2014,28(8):785-791.
[9]Zhao L,Chen X,Cai L,et al.Randomized,double-blind,placebo-controlled,multiple-dose study of the safty,tolerability and pharmacokinetics of benvitimod,a candidate drug for the treatment of psoriasis[J].J Clin Pharm Ther,2014,39(4):418-423.