A pharmacokinetic study of diphenhydramine transport across the blood-brain barrier in adult sheep: Potential involvement of a carrier-mediated mechanism
A pharmacokinetic study of diphenhydramine transport across the blood-brain barrier in adult sheep: Potential involvement of a carrier-mediated mechanism
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DOI：
10.1124/dmd.105.007898
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发表时间：
2006-06-01
影响因子：
3.9
通讯作者：
Riggs, K. Wayne
中科院分区：
文献类型：
--
作者：
Au-Yeung, Sam C. S.;Rurak, Dan W.;Riggs, K. Wayne
研究苯海拉明（DPHM）在绵羊血脑屏障（BBB）中的分布。在6只成年绵羊中，我们在两个实验中采用微透析技术研究了DPHM在脑细胞外液（ECF）和脑脊液（CSF）中的中枢神经系统（CNS）药代动力学。在第一个实验中，DPHM通过五步静脉输注（1.5、5.5、9.5、13.5和17.5 μ g/kg/min;每步7 h）给药。平均稳态CNS/总血浆浓度比（即，[CNS]/[总血浆]）的范围为0.4至0.5。然而，平均稳态[CNS]/[游离血浆]比值范围为2 - 3，表明DPHM主动转运至CNS。血浆蛋白结合率平均为86.1 +/- 2.3%（平均值+/- S. D.）的并且不随药物剂量的增加而改变。血浆、CSF和ECF表现出双指数药代动力学，终末消除半衰期（t（1/2 β））分别为10.8 +/- 5.4、3.6 +/- 1.0和5.3 +/- 4.2 h。CSF的大量流动和DPHM的转运介导的外排可以解释观察到的较高CNS清除率。在第二个实验中，DPHM与普萘洛尔（PRN）共同给药，以检查其对血脑CSF和血脑ECF DPHM关系的影响。PRN期间血浆总DPHM浓度降低12.8 +/- 6.3%，而ECF和CSF浓度升高（分别为88.1 +/- 45.4和91.6 +/-34.3%）。这种增加可能是由于PRN对DPHM脑消除的转运蛋白介导的外排机制的抑制作用。
The purpose of this study was to examine the disposition of diphenhydramine (DPHM) across the ovine blood-brain barrier (BBB). In six adult sheep, we characterized the central nervous system (CNS) pharmacokinetics of DPHM in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) using microdialysis in two experiments. In the first experiment, DPHM was administered via a five-step i.v. infusion (1.5, 5.5, 9.5, 13.5, and 17.5 mu g/kg/min; 7 h per step). Average steady-state CNS/total plasma concentration ratios (i.e., [CNS]/[total plasma]) for steps 1 to 5 ranged from 0.4 to 0.5. However, average steady-state [CNS]/[free plasma] ratios ranged from 2 to 3, suggesting active transport of DPHM into the CNS. Plasma protein binding averaged 86.1 +/- 2.3% (mean +/- S. D.) and was not altered with increasing drug dose. Plasma, CSF, and ECF demonstrated biexponential pharmacokinetics with terminal elimination half-lives (t(1/2 beta)) of 10.8 +/- 5.4, 3.6 +/- 1.0, and 5.3 +/- 4.2 h, respectively. The bulk flow of CSF and transport-mediated efflux of DPHM may explain the observed higher CNS clearances. In the second experiment, DPHM was coadministered with propranolol (PRN) to examine its effect on blood-brain CSF and blood-brain ECF DPHM relationships. Plasma total DPHM concentration decreased by 12.8 +/- 6.3% during PRN, whereas ECF and CSF concentrations increased (88.1 +/- 45.4 and 91.6 +/- 34.3%, respectively). This increase may be due to the inhibitory effect of PRN on a transporter-mediated efflux mechanism for DPHM brain elimination.