药学学报

Tissue	Regression equation	R²	Linear range /ng·mL^-1	LLOQ /ng·mL^-1
Plasma	Y = 0.007 5 X+0.016 5	0.999 8	4-1 024	4
Brain	Y = 0.007 4 X+0.037 9	0.997 3	5-500	5
Liver	Y = 0.008 4 X+0.239 5	0.998 0	5-1 600	5
Kidney	Y = 0.009 4 X+0.189 3	0.991 5	5-800	5

Tissue	Regression equation	R²	Linear range /ng·mL^-1	LLOQ /ng·mL^-1
Plasma	Y = 0.007 5 X+0.016 5	0.999 8	4-1 024	4
Brain	Y = 0.007 4 X+0.037 9	0.997 3	5-500	5
Liver	Y = 0.008 4 X+0.239 5	0.998 0	5-1 600	5
Kidney	Y = 0.009 4 X+0.189 3	0.991 5	5-800	5

Parameter	Administration group
AUC_{0- t} /μg·h·L^-1	1 214.4 ± 335.6	1 528.2 ± 442.7	2 377.1 ± 435.3^**
AUC_0-∞ /μg·h·L^-1	1 220.2 ± 328.0	1 561.2 ± 439.5	2 413.8 ± 448.9^**
MRT_{0- t} /h	4.3 ± 0.9	4.5 ± 0.5	5.1 ± 0.4
MRT_0-∞ /h	4.5 ± 1.2	5.2 ± 0.7	5.5 ± 0.9^*
t_1/2z /h	2.6 ± 1.8	4.3 ± 2.0	3.7 ± 1.3^*
t_max /h	0.75 ± 0.25	0.85 ± 0.5	0.60 ± 0.3
C_max /μg·L^-1	422.0 ± 192.0	382.9 ± 74.3	470.3 ± 66.7

Parameter	Administration group
AUC_{0- t} /μg·h·L^-1	1 214.4 ± 335.6	1 528.2 ± 442.7	2 377.1 ± 435.3^**
AUC_0-∞ /μg·h·L^-1	1 220.2 ± 328.0	1 561.2 ± 439.5	2 413.8 ± 448.9^**
MRT_{0- t} /h	4.3 ± 0.9	4.5 ± 0.5	5.1 ± 0.4
MRT_0-∞ /h	4.5 ± 1.2	5.2 ± 0.7	5.5 ± 0.9^*
t_1/2z /h	2.6 ± 1.8	4.3 ± 2.0	3.7 ± 1.3^*
t_max /h	0.75 ± 0.25	0.85 ± 0.5	0.60 ± 0.3
C_max /μg·L^-1	422.0 ± 192.0	382.9 ± 74.3	470.3 ± 66.7

Sample	AUC_0.3 _- _{14.8 h}/ng·h·g^-1		Ratio		AUC_0.375 _- _{10.4 h}/ng·h·g^-1		Ratio
Plasma^#	1 105.9	2 205.9		2.0		1 102.7	2 051.5	1.9
Brain	2 833.8	3 651.4	1.3	2 719.1	3 195.2	1.2
Liver	11 853.5	17 816.2	1.5	11 128.0	15 055.7	1.4
Kidney	6 170.4	9 225.1	1.5	5 800.8	7 824.5	1.3

Sample	AUC_0.3 _- _{14.8 h}/ng·h·g^-1		Ratio		AUC_0.375 _- _{10.4 h}/ng·h·g^-1		Ratio
Plasma^#	1 105.9	2 205.9		2.0		1 102.7	2 051.5	1.9
Brain	2 833.8	3 651.4	1.3	2 719.1	3 195.2	1.2
Liver	11 853.5	17 816.2	1.5	11 128.0	15 055.7	1.4
Kidney	6 170.4	9 225.1	1.5	5 800.8	7 824.5	1.3

冰片对大鼠体内长春西汀药动学的影响

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王恩莹 ^# , 金成婷 ^# , 王俊俊 , 陈勇 , 韩凤梅 ^*

药学学报 | 研究论文 2019,54(11): 2064-2068

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药学学报 |研究论文 2019 , 54 (11) : 2064 -2068

冰片对大鼠体内长春西汀药动学的影响

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王恩莹^#, 金成婷^#, 王俊俊, 陈勇, 韩凤梅^*

作者信息

湖北大学中药生物技术省重点实验室, 药物高通量筛选技术国家地方联合工程研究中心, 湖北武汉 430062

通讯作者:

*韩凤梅 ,Tel/Fax: 86-027-88663590, E-mail: 1597114874@qq.com

Effects of borneol on the pharmacokinetics of vinpocetine in rats

En-ying WANG, Cheng-ting JIN, Jun-jun WANG, Yong CHEN, Feng-mei HAN^*

Affiliations

Hubei Province Key Laboratory of Biotechnology of Traditional Chinese Medicine, National&Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China

出版时间: 2019-11-12 doi: 10.16438/j.0513-4870.2019-0339

文章导航

摘要

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长春西汀（vinpocetine，VP）被广泛应用于脑血管功能障碍和神经损伤的治疗，而传统中药冰片（borneol，BN）常用于促进治疗中枢神经系统疾病的药物的吸收与分布。本文旨在研究BN对VP药动学和组织分布的影响。健康SD大鼠随机分成3组，分别灌胃VP（10 mg·kg^-1）、VP+BN（10 mg·kg^-1+150mg·kg^-1）及VP+BN（10 mg·kg^-1+75 mg·kg^-1）进行药动学研究。另设两组分别灌胃VP（10 mg·kg^-1）及VP+BN（10 mg·kg^-1+150mg·kg^-1）进行组织分布研究。动物实验经湖北大学伦理委员会批准，遵循实验动物管理条例的规定。采用LC-MS/MS法检测血浆及组织中VP的浓度，计算其药动学参数。与VP单用组相比，高剂量联合用药组VP的AUC_0-∞、MRT_0-∞及t_1/2z分别显著提高1.98、1.22和1.42倍；肝、肾、脑组织暴露量分别增加1.5、1.5和1.3倍。联合使用BN和VP有助于改善VP平均驻留时间短、口服生物利用度低、脑暴露低等不良药动学特征。

关键词

长春西汀 / 冰片 / 药动学 / 组织分布

Abstract

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Vinpocetine (VP) has been widely used to treat cerebrovascular disorders and nerve injury. Borneol (BN), as an important traditional Chinese medicine, is commonly used to promote the absorption and distribution of central nervous system drugs. In this work, a LC-MS/MS method was developed to determine the level of VP in rat plasma and tissues, and to evaluate the effect of co-administration of BN with VP by oral gavage on the absorption and tissue distribution of VP in rats. Rats were divided into VP (10 mg·kg^-1), VP (10 mg·kg^-1) + BN (75 mg·kg^-1) and VP (10 mg·kg^-1) + BN (150 mg·kg^-1) groups for pharmacokinetic study, and divided into VP (10 mg·kg^-1) and VP (10 mg·kg^-1) + BN (150 mg·kg^-1) groups for tissue distribution study. The animal experiment was approved by Ethics Committee of Hubei University, and complied with the guideline for caring and using of laboratory animals. Compared to VP group, the AUC_0-∞, MRT_0-∞ and t_1/2z of VP + BN (150 mg·kg^-1) group increased significantly, by 1.98-, 1.22- and 1.42-fold respectively, and the exposure in plasma, liver, kidney and brain increased by 2-, 1.5-, 1.5- and 1.3-fold respectively. The pharmacokinetic results suggested that co-administration of BN with VP is beneficial for overcoming the undesirable pharmacokinetic characteristics of VP, such as short residence time, low oral bioavailability and brain exposure in clinical usage.

Key words

vinpocetine / borneol / pharmacokinetics / tissue distribution

引用本文

王恩莹, 金成婷, 王俊俊, 陈勇, 韩凤梅. 冰片对大鼠体内长春西汀药动学的影响. 药学学报, 2019 , 54 (11) : 2064 -2068 . DOI: 10.16438/j.0513-4870.2019-0339

En-ying WANG, Cheng-ting JIN, Jun-jun WANG, Yong CHEN, Feng-mei HAN. Effects of borneol on the pharmacokinetics of vinpocetine in rats[J]. Acta Pharmaceutica Sinica, 2019 , 54 (11) : 2064 -2068 . DOI: 10.16438/j.0513-4870.2019-0339

正文

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长春西汀(vinpocetine, VP, 图 1)是一种长春胺的半合成生物碱类衍生物, 被广泛地应用于慢性脑血管缺血、脑动脉硬化、老年脑功能障碍等脑血管疾病的治疗^{[1, 2]}。此外, VP在体内还有具有良好的神经保护作用, 如抗缺氧、抗健忘症和抗缺血作用等^{[3, 4]}。

药动学研究表明, 由于存在明显的首过效应, VP的口服生物利用度低^[5], 血浆蛋白结合率约为86.6%, 消除半衰期(t_1/2z)为1~2 h^[6]。VP可以通过血脑屏障, 但是脑内暴露量很低^[7]。由于口服生物利用度差(~6.7%), t_1/2z (1~2 h)短, 肝脏首过效应明显(~75%), VP在临床上以静脉注射给药为主, 口服给药受到很大限制^[5]。因此为了提高VP的生物利用度或其脑组织的靶向分布, 近年来研究者们开发了大量关于对VP的新的给药系统与方法, 如口服固体脂质纳米粒^{[8, 9]}, 经皮给药的微乳液或前脂质体^[10-12]等, 这些给药系统不仅可以在一定程度上提高VP的生物利用度, 而且具有控释、靶向作用。但这些方法制备工艺复杂、有载药量受限、制剂突释等缺点, 因此, 有必要探索一种更方便、更有效的方法来增加VP的口服吸收及靶向分布。

冰片(borneol, BN, 图 1)是一种高脂溶性双环萜类化合物, 是治疗心脑血管疾病常用的中药成分(如复方丹参滴丸), 现代研究^[13]也证实, BN对脑缺血损伤具有保护作用, 尤其是左旋BN作用最强, 因此在临床上有与VP联用以增强治疗效果的可能性。同时, BN能增加膜的通透性, 抑制细胞膜上P-gp的活性^[14-16], 可作为渗透增强剂增加部分药物的口服吸收^{[17, 18]}和脑暴露量^{[14, 15, 19]}, 本研究旨在考察联合灌胃给药, BN对大鼠VP的口服吸收及组织分布的影响。

材料与方法

收起

药品与试剂 VP(纯度≥98%, 批号: 20151124)购于武汉泰凯塞公司, (-)-BN (纯度≥97%, 批号: 10176312)和内标(IS)非那西丁(纯度≥97%, 批号: 10104615)购于美国阿法埃莎公司, 甲酸(质谱级, 批号: BCBK1263V)和Tween-80购于美国Sigma公司, 乙腈(色谱级, 批号: 131937)购于美国Fischer公司, 乙酸乙酯(分析纯, 批号: 20160721)购于SCR沪试公司。

实验动物 68只雄性SD大鼠(220 ± 25 g)购于湖北省疾病预防控制中心, 许可证号SCXK (鄂) 2011-0012, 于湖北大学SPF级动物房中适应性饲养1周后进行实验(饲养间采用12 h明暗间隔的照明控制, 饲养温度保持在24 ± 2 ℃, 湿度保持在65% ± 5%)。动物实验经湖北大学伦理委员会批准, 实验过程遵循实验动物管理条例的规定。

LC-MS/MS条件 液质联用仪系统包括LC-30 AD二元泵、SPD-M20A检测器、CTO-20AC柱温箱、SIL-30AC自动进样器、DGU-20A5在线真空脱气机, Shim-pack XR-ODS Ⅲ C18柱(75 mm×2.0 mm, 1.6 μm)和Shim-pack保护柱(2.0 mm×5.0 mm, 4.6 μm)购于日本岛津公司。以0.1%甲酸-水(A)和乙腈(B)为流动相, A:B = 70:30, 等度洗脱, 流速为0.4 mL·min^-1, 进样体积10 μL, 采用ESI源以MRM+模式进行检测, VP的定量离子对为m/z 351.10→m/z 280.10, IS的定量离子对为m/z 180.00→m/z 110.15。加热模块温度400 ℃, DL管温度250 ℃, 雾化气(N₂)流速3.0 L·min^-1, 干燥气(N₂)流速15.0 L·min^-1。

样品处理

血浆样品精密吸取空白血浆45 μL, 向其中加入不同浓度VP工作液和IS工作液(125 ng·mL^-1)各2.5 μL, 混匀后, 加入乙酸乙酯500 μL进行萃取, 震荡6 min, 以12 000 r·min^-1离心10 min, 取上清400 μL于1.5 mL离心管中, 于浓缩仪中挥干。

组织样品精密吸取空白组织匀浆90 μL, 加入不同浓度VP工作液和IS工作液(125 ng·mL^-1)各5 μL, 混匀后加入乙酸乙酯500 μL, 涡旋混匀6 min后, 15 000 r·min^-1离心10 min, 取上清400 μL置于1.5 mL离心管中, 于浓缩仪中挥干。

方法学考察

专属性通过比较空白大鼠血浆/组织匀浆、加入VP对照品和IS的血浆/组织匀浆及加入IS的血浆/组织匀浆样品的MRM总离子流图谱, 考察方法的专属性。

线性关系通过向空白大鼠血浆/组织匀浆中加入一系列不同浓度的VP工作液(血浆: 4、8、64、256、409.6、819.2和1 024 ng·mL^-1; 脑: 5、10、40、100、200、400和500 ng·mL^-1; 肝: 5、10、50、200、800、1 280和1 600 ng·mL^-1; 肾: 5、10、50、200、400、640和800 ng·mL^-1), 按“样品处理”项下方法处理样品, 评价其线性。

精密度同一天和连续三天检测低、中、高三浓度的质控样品(n = 6), 考察方法的准确度(相对回收率)和日内/日间精密度(以RSD表示)。

回收率比较处理后低、中、高浓度的质控样品与处理后空白基质中添加相同浓度的对照品(n = 6)的峰面积, 考察提取回收率。

基质效应比较血浆/组织匀浆存在时的峰面积与纯溶剂中VP的峰面积(n = 6)考察基质效应。

稳定性比较低、高浓度的质控样品(n = 6)经下列条件处理后的检测浓度与理论浓度的比值, 考察①室温放置4 h, ② -80 ℃放置20天, ③ -80 ℃三次冻融循环, ④ 4 ℃进样器放置8 h, 样品的稳定性。

药动学研究 18只健康雄性SD大鼠(体重220 ± 25 g)随机分为3组, 分别为VP单用组(10 mg·kg^-1)、VP与低剂量BN合用组(VP 10 mg·kg^-1+BN 75 mg·kg^-1)以及VP与高剂量BN合用组(VP 10 mg·kg^-1 + BN 150 mg·kg^-1), 每组6只(n = 6)。将VP及BN混悬在0.5% CMC-Na (含1%吐温-80)中, 使VP终浓度为1 g·L^-1, BN终浓度为7.5和15 g·L^-1, 灌胃体积为10 mL·kg^-1。大鼠禁食12 h后, 按上述剂量灌胃给药, 分别于0.12、0.25、0.5、0.75、1、1.5、3.5、5.5、8、11、14和24 h经大鼠眼眶的静脉丛处取血0.3 mL, 置于已肝素化的1.5 mL EP管中, 4 ℃条件下静置30 min后, 以4 000 r·min^-1离心10 min, 取上清液即得到血浆, 于-80 ℃冰箱保存。按“样品处理”项下方法处理样品后, 残渣用流动相100 μL复溶, 涡旋振荡仪充分震荡6 min, 12 000 r·min^-1离心10 min, 取上清液10 μL LC-MS/MS检测样品浓度。使用DAS 3.0软件以非房室模型进行拟合, 计算出VP在大鼠体内的药动学参数。

组织分布研究 将50只健康雄性SD大鼠(体重220 ± 25 g)随机分为两个给药组, 每个给药组再分别分为5个时间组, 每组5只(n = 5)。给药组分别为: VP组(10 mg·kg^-1)以及VP (10 mg·kg^-1)与高剂量BN (150 mg·kg^-1)合用组。按上述剂量给药后, 分别于吸收相、平衡相、消除相所对应的时间点取血, 处死后取肝、肾、脑组织。对VP单用组, 对应的取样点为0.375、0.75、2.6、5.2和10.4 h; 对VP、BN合用组, 对应的取样点为0.3、0.6、3.7、7.4和14.8 h。用冰冷的生理盐水冲洗各组织, 滤纸吸干水分, 称重后用剪刀剪碎, 按照肝、肾(w/v, 1:6), 脑(w/v, 1:4)的比例在冰冷的生理盐水中进行匀浆, 置于-80 ℃冰箱保存。

按照“样品处理”项下方法处理样品, 残渣中加入流动相100 μL涡旋振荡复溶, 15 000 r·min^-1离心10 min, 取上清液10 μL进行LC-MS/MS检测。用DAS 3.0软件以梯形面积法计算AUC_0-t。

统计学分析 实验结果以mean ± SD表示, 采用SPSS 13.0软件进行双尾t检验。

结果

收起

1 方法学考察

结果表明, VP和IS分离良好, 且在空白血浆及各组织匀浆中的内源性物质不会干扰待测物和内标的检测, 专属性良好。以血浆为例, MRM模式下的VP及IS的总离子流色谱图见图 2。

VP在血浆, 肝、肾、脑组织匀浆中的线性方程、线性范围及LLOQ见表 1, 结果表明VP在血浆及肝、肾、脑匀浆中, 分别在4~1 024、5~500、5~1 600和5~800 ng·mL^-1浓度内线性良好, 且VP在血浆及组织匀浆中的LLOQ分别为4和5 ng·mL^-1。

日内、日间精密度及准确度结果表明, 低、中、高3个浓度的质控样品的RSD均在1.3%~9.3%以内, 准确度在85.2%~103.7%之间。提取回收率在86.5%~106.7%之间, 基质效应在85.3%~109.3%之间, 满足实验要求。

低、高浓度的质控样品在室温放置4 h, 4 ℃进样器中放置8 h, -80 ℃冰箱放置20天以及-80 ℃反复冻融循环3次的条件下, 准确度均在-9.80%~11.1%之间, 表明样品在上述条件下稳定。

2 药动学研究

VP的平均血浆药物浓度-时间曲线见图 3A, 药动学参数见表 2。结果表明, 与VP单用组相比, VP联合高剂量BN给药组的曲线下面积AUC_0-∞、平均驻留时间MRT_0-∞和清除半衰期t_1/2z均显著增大, 分别为VP单用组的1.98倍、1.22倍和1.42倍。此外, VP与高剂量BN联合用药组的C_max增加、达峰时间t_max减小, 但是与VP单用组相比没有显著性差异。以上结果表明BN可以增加VP在大鼠体内的药物量, 且能减缓VP的消除。

3 组织分布研究

VP在组织匀浆中的平均药物浓度-时间曲线见图 3B~D, 在各组织中的暴露量分别以AUC_0.3_{-14.8 h}和AUC_0.375_{-10.4 h}进行计算, 结果见表 3。与VP单用组相比, VP与高剂量BN合用后, VP在血浆和各组织中的暴露量均增加了, 且脑 < 肾 < 肝 < 血浆。以上结果表明BN能促进VP的组织分布。

讨论

收起

本文建立了快速、灵敏的LC-MS/MS方法检测生物样品中VP的含量, 并成功将其应用到大鼠血浆及肝、肾、脑组织中VP的检测。结果表明, 联合使用BN和VP, 有助于改善VP平均驻留时间短、口服生物利用度低、脑暴露低等不良药动学特征。VP的主要吸收部位在小肠^[20], 而BN是良好的胃肠道吸收促进剂, 它能够抑制小肠中药物外排转运体P-gp、MRP的活性^{[15, 16, 21]}, 从而增加药物的吸收量; 同时, BN能够可逆的下调与细胞紧密连接相关的基因的表达, 提高药物经细胞旁路转运的量^[22], 因此BN可能是通过以上途径增强VP的肠吸收, 使VP的体内药物量增加。

VP有明显的肝脏首过效应, 有研究^{[23, 24]}表明BN能够抑制肝脏葡萄糖醛酸转移酶、CYP3A的酶活, 因此可能会抑制VP在肝脏的代谢, 此外, BN能够提高血管壁通透性, 使药物更容易穿过血管壁进入组织^[24], 以上可能是VP在肝、肾、脑中的暴露量也有不同程度增加的原因。由于BN促进吸收、分布的原因很复杂, 因此其对VP吸收、分布影响的具体机制还需要进一步的深入研究。

参考文献

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2019年第54卷第11期

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doi: 10.16438/j.0513-4870.2019-0339

接收时间：2019-04-28
首发时间：2026-01-26
出版时间：2019-11-12

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收稿日期：2019-04-28
修回日期：2019-06-04

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湖北大学中药生物技术省重点实验室, 药物高通量筛选技术国家地方联合工程研究中心, 湖北武汉 430062

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*韩凤梅 ,Tel/Fax: 86-027-88663590, E-mail: 1597114874@qq.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Tissue	Regression equation	R²	Linear range /ng·mL^-1	LLOQ /ng·mL^-1
Plasma	Y = 0.007 5 X+0.016 5	0.999 8	4-1 024	4
Brain	Y = 0.007 4 X+0.037 9	0.997 3	5-500	5
Liver	Y = 0.008 4 X+0.239 5	0.998 0	5-1 600	5
Kidney	Y = 0.009 4 X+0.189 3	0.991 5	5-800	5

Tissue

Regression equation

R²

Linear range
/ng·mL^-1

LLOQ
/ng·mL^-1

Plasma

Y = 0.007 5 X+0.016 5

0.999 8

4-1 024

Brain

Y = 0.007 4 X+0.037 9

0.997 3

5-500

Liver

Y = 0.008 4 X+0.239 5

0.998 0

5-1 600

Kidney

Y = 0.009 4 X+0.189 3

0.991 5

5-800

Parameter	Administration group
AUC_{0- t} /μg·h·L^-1	1 214.4 ± 335.6	1 528.2 ± 442.7	2 377.1 ± 435.3^**
AUC_0-∞ /μg·h·L^-1	1 220.2 ± 328.0	1 561.2 ± 439.5	2 413.8 ± 448.9^**
MRT_{0- t} /h	4.3 ± 0.9	4.5 ± 0.5	5.1 ± 0.4
MRT_0-∞ /h	4.5 ± 1.2	5.2 ± 0.7	5.5 ± 0.9^*
t_1/2z /h	2.6 ± 1.8	4.3 ± 2.0	3.7 ± 1.3^*
t_max /h	0.75 ± 0.25	0.85 ± 0.5	0.60 ± 0.3
C_max /μg·L^-1	422.0 ± 192.0	382.9 ± 74.3	470.3 ± 66.7

Parameter

Administration group

VP (10 mg·kg^-1)

VP (10 mg·kg^-1) + BN (75 mg·kg^-1)

VP (10 mg·kg^-1) + BN (150 mg·kg^-1)

AUC_{0- t} /μg·h·L^-1

1 214.4 ± 335.6

1 528.2 ± 442.7

2 377.1 ± 435.3^**

AUC_0-∞ /μg·h·L^-1

1 220.2 ± 328.0

1 561.2 ± 439.5

2 413.8 ± 448.9^**

MRT_{0- t} /h

4.3 ± 0.9

4.5 ± 0.5

5.1 ± 0.4

MRT_0-∞ /h

4.5 ± 1.2

5.2 ± 0.7

5.5 ± 0.9^*

t_1/2z /h

2.6 ± 1.8

4.3 ± 2.0

3.7 ± 1.3^*

t_max /h

0.75 ± 0.25

0.85 ± 0.5

0.60 ± 0.3

C_max /μg·L^-1

422.0 ± 192.0

382.9 ± 74.3

470.3 ± 66.7

Sample	AUC_0.3 _- _{14.8 h}/ng·h·g^-1		Ratio		AUC_0.375 _- _{10.4 h}/ng·h·g^-1		Ratio
Plasma^#	1 105.9	2 205.9		2.0		1 102.7	2 051.5	1.9
Brain	2 833.8	3 651.4	1.3	2 719.1	3 195.2	1.2
Liver	11 853.5	17 816.2	1.5	11 128.0	15 055.7	1.4
Kidney	6 170.4	9 225.1	1.5	5 800.8	7 824.5	1.3

Sample

AUC_0.3 _- _{14.8 h}/ng·h·g^-1

Ratio

AUC_0.375 _- _{10.4 h}/ng·h·g^-1

Ratio

b/a

Plasma^#

1 105.9

2 205.9

2.0

1 102.7

2 051.5

1.9

Brain

2 833.8

3 651.4

1.3

2 719.1

3 195.2

1.2

Liver

11 853.5

17 816.2

1.5

11 128.0

15 055.7

1.4

Kidney

6 170.4

9 225.1

1.5

5 800.8

7 824.5

1.3