Pharmacokinetics and Metabolism of 4R-Cembranoid.
Pharmacokinetics and Metabolism of 4R-Cembranoid.
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DOI：
10.1371/journal.pone.0121540
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ferchmin PA
中科院分区：
文献类型：
--
作者：
Vélez-Carrasco W;Green CE;Catz P;Furimsky A;O'Loughlin K;Eterović VA;Ferchmin PA
4R-cembranoid （4R）是烟叶中发现的一种天然环二萜，具有神经保护活性。4R对大鼠海马切片NMDA、对氧磷（POX）和二异丙基氟磷酸（DFP）损伤有保护作用，对大鼠体内DFP也有保护作用。本研究的目的是研究4R的代谢和药代动力学，作为其作为神经保护药物临床前开发的一部分。发现10µM 4R在血浆中非常稳定，潜伏期长达1小时。人微粒体中4R代谢比大鼠快。在微粒体样本中检测到10种4R代谢物；4R的6种二羟基和4种单羟基形式。雄性大鼠单次给药4R，剂量为6mg /kg，静脉、内、皮下注射，静脉注射组血药浓度最高，为1017 ng/mL。t1/2为36分钟，10分钟内到达大脑。脑内峰值浓度为6516 ng/g。im组血药浓度峰值为163 ng/mL， sc组血药浓度峰值为138 ng/mL。静脉注射和静脉注射后4R的t1/2约为1.5小时。脑峰值浓度分别为329 ng/g和323 ng/g。在给药后10 min，静脉注射组脑血浆比为6.4，而在给药后90 min，静脉注射组和s.c.组脑血浆比分别为2.49和2.48。我们的数据显示，4R穿过血脑屏障，集中在大脑中发挥其神经保护作用。
4R-cembranoid (4R) is a natural cyclic diterpenoid found in tobacco leaves that displays neuroprotective activity. 4R protects against NMDA, paraoxon (POX), and diisopropylfluorophosphate (DFP) damage in rat hippocampal slices and against DFP in rats in vivo. The purpose of this study was to examine the metabolism and pharmacokinetics of 4R as part of its preclinical development as a neuroprotective drug. 10 µM 4R was found to be very stable in plasma for up to 1 hr incubation. 4R metabolism in human microsomes was faster than in the rat. Ten metabolites of 4R were detected in the microsomal samples; 6 dihydroxy and 4 monohydroxy forms of 4R. Male rats received a single dose of 4R at 6 mg/kg i.v., i.m., or s.c. The i.v. group had the highest plasma concentration of 1017 ng/mL. The t1/2 was 36 min and reached the brain within 10 min. The brain peak concentration was 6516 ng/g. The peak plasma concentration in the i.m. group was 163 ng/mL compared to 138 ng/mL in the s.c. group. The t1/2 of 4R after i.m. and s.c. administration was approximately 1.5 hr. The brain peak concentration was 329 ng/g in the i.m. group and 323 ng/g for the s.c. group. The brain to plasma ratio in the i.v. group was 6.4, reached 10 min after dose, whereas in the i.m. and s.c. groups was 2.49 and 2.48, respectively, at 90 min after dose. Our data show that 4R crosses the BBB and concentrates in the brain where it exerts its neuroprotective effect.
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DOI：
10.3891/acta.chem.scand.46-0367
发表时间：
1992-04-01
期刊：
ACTA CHEMICA SCANDINAVICA
影响因子：
--
作者：
EKLUND, AM;BERG, JE;WAHLBERG, I
通讯作者：
WAHLBERG, I
影响因子：
3.2
作者：
Smith, DJ;Martin, VJJ;Mohn, WW
通讯作者：
Mohn, WW
影响因子：
12.3
作者：
通讯作者：
--
影响因子：
3.9
作者：
Patki, KC;von Moltke, LL;Greenblatt, DJ
通讯作者：
Greenblatt, DJ
影响因子：
3.6
作者：
ROBERTS, DL;ROWLAND, RL
通讯作者：
ROWLAND, RL