盐酸特比萘芬片在犬体内的药动学及绝对生物利用度研究
发布时间：2019-03-27 09:36
【摘要】：盐酸特比萘芬是第二代丙烯胺类广谱抗真菌药,具有抗真菌机制明确、抗真菌谱广、疗效确切、剂型多、适用性广等特点,目前已在人医临床广泛应用,但在动物方面的研究仍较少。本试验旨在通过对犬进行盐酸特比萘芬注射液注射和盐酸特比萘芬片口服给药,以获得相关药动学参数,了解特比萘芬在犬体内的药代动力学过程及绝对生物利用度,为兽医临床制定合理的给药方案及有效降低不良反应,提供理论依据。8只体重较一致的健康比格犬采用交叉试验设计,随机分为两组,每组4只(公母各半)。第一阶段,第一组犬单剂量(5 mg/kg bw)静脉注射2%盐酸特比萘芬注射液,第二组犬单剂量(20 mg/kg bw)口服盐酸特比萘芬片;第二阶段,第一组犬单剂量(20 mg/kg bw)口服盐酸特比萘芬片,第二组犬单剂量(5 mg/kg bw)静脉注射2%盐酸特比萘芬注射液,两阶段洗脱期为2周。另设一平行较低剂量口服给药组,即8只犬单剂量(10 mg/kg bw)口服盐酸特比萘芬片。给药后按预定时间采集血样。血浆中特比萘芬含量采用高效液相色谱串联二极管阵列检测器(HPLC-DAD)进行检测分析,流动相为甲醇-0.1%磷酸水溶液(59:41,V/V)。外标法定量。特比萘芬的实测血药浓度-时间数据采用WinNonlin5.2版药动学分析软件计算药代动力学参数。单剂量(5 mg/kg bw)静脉注射2%盐酸特比萘芬注射液后,特比萘芬在犬体内的平均消除半衰期(T1/2)约为15.16 h,平均滞留时间(MRT)约为2.44 h,药物从零时间至24 h的平均药时曲线下面积(AUC0～24h)约为1.80 μg·h/mL,平均表观分布容积(Vd)约为49.78 L/kg,平均血浆清除率(CL)约为2.42 L/(kg·h)。犬单剂量10 mg//kg bw和20 mg/kg bw口服盐酸特比萘芬片后,特比萘芬在犬体内T1/2分别为19.25和18.15 h,平均达峰时间(Tmax)分别为1.69和1.88h,平均达峰浓度(Cmax)分别为0.16和0.32μg/mL,MRT分别为5.22和5.02 h;AUC0～24h分别为0.62和1.09μg·h/mL;按AUC0～24h估算,平均绝对生物利用度(F0～24h)分别为17.08%和16.59%。结果表明,特比萘芬在犬体内分布广泛,消除缓慢;犬口服盐酸特比萘芬片吸收迅速,但吸收不完全;犬单剂量10 mg//kg bw和20 mg/kg bw 口服盐酸特比萘芬片,达峰时间、消除半衰期、平均滞留时间和生物利用度均无显著差异,但达峰浓度和药时曲线下面积成比例增加,具剂量相关性。
[Abstract]:Terbinafine hydrochloride is the second generation broad-spectrum antifungal drug of propenylamine, which has the characteristics of clear antifungal mechanism, wide antifungal spectrum, definite curative effect, multiple dosage forms and wide applicability, and has been widely used in human medicine at present. However, there is still little research on animals. The aim of this study was to obtain the relevant pharmacokinetic parameters by injection of terbinafine hydrochloride injection and oral administration of terbinafine hydrochloride tablets in dogs, and to understand the pharmacokinetics and absolute bioavailability of terbinafine in dogs. Eight healthy Beagle dogs with the same body weight were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy beagle dogs were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy Beagle dogs with consistent weight were randomly divided into two groups, 4 in each group (half male and female). In the first stage, 2% terbinafine hydrochloride was administered intravenously to dogs in the first group (5 mg/kg bw), and the second group was given terbinafine hydrochloride tablets orally at 20 mg/kg bw. In the second stage, a single dose (20 mg/kg bw) of terbinafine hydrochloride tablets was given to dogs in the first group, and a 2% terbinafine hydrochloride injection was injected intravenously in the second group (5 mg/kg bw). The two-stage elution period was 2 weeks. In addition, 8 dogs were given terbinafine hydrochloride tablets at a single dose (10 mg/kg bw) in a parallel lower dose oral administration group. Blood samples were collected at the scheduled time after administration. Terbinafine in plasma was determined by high performance liquid chromatography series diode array detector (HPLC-DAD). The mobile phase consisted of methanol-0.1% phosphoric acid aqueous solution (59 脳 41, V 路V). The external standard method was used for quantitative analysis. The pharmacokinetic parameters of terbinafine were calculated by pharmacokinetic analysis software WinNonlin5.2. After intravenous injection of 2% terbinafine hydrochloride (5 mg/kg bw), the average elimination half life (T 1) of terbinafine was about 15.16 h and the mean retention time (MRT) of terbinafine was about 2.44 h. The average area under the curve (AUC0~24h) of the drug from zero to 24 hours was about 1.80 渭 g 路h / mL, and the average apparent distribution volume (Vd) was about 49.78 L 路kg ~ (- 1). The mean plasma clearance rate (CL) was about 2.42 L / (kg 路h). After oral administration of terbinafine hydrochloride tablets for 10 mg//kg bw and 20 mg/kg bw in dogs, the T _ (1) O _ (2) of terbinafine was 19.25 and 18.15 h, and the average peak time (Tmax) was 1.69 and 1.88 h, respectively, and the mean peak time of terbinafine was 1.69 and 1.88 h respectively. The average peak concentrations (Cmax) were 0.16 渭 g / mL,MRT and 0.32 渭 g / mL,MRT for 5.22 and 5.02 h, respectively. The AUC0~24h values were 0.62 and 1.09 渭 g 路h / mL;, respectively, and the mean absolute bioavailability (F0 / 24h) was 17.08% and 16.59%, respectively, according to AUC0~24h. The results showed that terbinafine was widely distributed in dogs and its elimination was slow, and that terbinafine hydrochloride tablets were absorbed quickly but not completely by oral administration of terbinafine hydrochloride in dogs. There was no significant difference in peak-reaching time, elimination half-life, average retention time and bioavailability of terbinafine hydrochloride tablets at a single dose of 10 mg//kg bw and 20 mg/kg bw in dogs, but the peak concentration and area under the drug-time curve increased proportionally. There was dose-dependent.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S859.7
[Abstract]:Terbinafine hydrochloride is the second generation broad-spectrum antifungal drug of propenylamine, which has the characteristics of clear antifungal mechanism, wide antifungal spectrum, definite curative effect, multiple dosage forms and wide applicability, and has been widely used in human medicine at present. However, there is still little research on animals. The aim of this study was to obtain the relevant pharmacokinetic parameters by injection of terbinafine hydrochloride injection and oral administration of terbinafine hydrochloride tablets in dogs, and to understand the pharmacokinetics and absolute bioavailability of terbinafine in dogs. Eight healthy Beagle dogs with the same body weight were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy beagle dogs were randomly divided into two groups, 4 in each group (half male and female), and 8 healthy Beagle dogs with consistent weight were randomly divided into two groups, 4 in each group (half male and female). In the first stage, 2% terbinafine hydrochloride was administered intravenously to dogs in the first group (5 mg/kg bw), and the second group was given terbinafine hydrochloride tablets orally at 20 mg/kg bw. In the second stage, a single dose (20 mg/kg bw) of terbinafine hydrochloride tablets was given to dogs in the first group, and a 2% terbinafine hydrochloride injection was injected intravenously in the second group (5 mg/kg bw). The two-stage elution period was 2 weeks. In addition, 8 dogs were given terbinafine hydrochloride tablets at a single dose (10 mg/kg bw) in a parallel lower dose oral administration group. Blood samples were collected at the scheduled time after administration. Terbinafine in plasma was determined by high performance liquid chromatography series diode array detector (HPLC-DAD). The mobile phase consisted of methanol-0.1% phosphoric acid aqueous solution (59 脳 41, V 路V). The external standard method was used for quantitative analysis. The pharmacokinetic parameters of terbinafine were calculated by pharmacokinetic analysis software WinNonlin5.2. After intravenous injection of 2% terbinafine hydrochloride (5 mg/kg bw), the average elimination half life (T 1) of terbinafine was about 15.16 h and the mean retention time (MRT) of terbinafine was about 2.44 h. The average area under the curve (AUC0~24h) of the drug from zero to 24 hours was about 1.80 渭 g 路h / mL, and the average apparent distribution volume (Vd) was about 49.78 L 路kg ~ (- 1). The mean plasma clearance rate (CL) was about 2.42 L / (kg 路h). After oral administration of terbinafine hydrochloride tablets for 10 mg//kg bw and 20 mg/kg bw in dogs, the T _ (1) O _ (2) of terbinafine was 19.25 and 18.15 h, and the average peak time (Tmax) was 1.69 and 1.88 h, respectively, and the mean peak time of terbinafine was 1.69 and 1.88 h respectively. The average peak concentrations (Cmax) were 0.16 渭 g / mL,MRT and 0.32 渭 g / mL,MRT for 5.22 and 5.02 h, respectively. The AUC0~24h values were 0.62 and 1.09 渭 g 路h / mL;, respectively, and the mean absolute bioavailability (F0 / 24h) was 17.08% and 16.59%, respectively, according to AUC0~24h. The results showed that terbinafine was widely distributed in dogs and its elimination was slow, and that terbinafine hydrochloride tablets were absorbed quickly but not completely by oral administration of terbinafine hydrochloride in dogs. There was no significant difference in peak-reaching time, elimination half-life, average retention time and bioavailability of terbinafine hydrochloride tablets at a single dose of 10 mg//kg bw and 20 mg/kg bw in dogs, but the peak concentration and area under the drug-time curve increased proportionally. There was dose-dependent.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S859.7
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相关期刊论文 前10条
1 薛英;;犬皮肤病的诊治[J];中国工作犬业;2016年09期
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5 李t，
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