The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice
The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice
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DOI：
10.1002/jps.20344
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发表时间：
2005-06-01
影响因子：
3.8
通讯作者：
Ho, RJY
中科院分区：
文献类型：
--
作者：
Salama, NN;Kelly, EJ;Ho, RJY
蛋白酶抑制剂（如奈非那韦）浓度不足可能会降低HIV痴呆治疗的有效性。外排转运蛋白mdr 1产物P-糖蛋白（P-gp）已被证明在限制奈非那韦脑水平中发挥作用。本研究的目的是比较GF 120918（10 mg/kg，IV）（一种P-gp抑制剂）对P-gp活性mdr 1a/1b（+/+）小鼠与P-gp双敲除mdr 1a/1b小鼠中静脉内奈非那韦（10 mg/kg）体内处置和组织渗透的影响。mdr 1a/1b小鼠静脉注射P-gp抑制剂GF 120918可使奈非那韦浓度增加2.3- 27倍，而奈非那韦在mdr 1a/1b（-/-）小鼠中的分布比野生小鼠高2- 16倍。与mdr 1a/1b基因敲除小鼠相比，GF 120918联合给药后，心脏、肝脏和肾脏中的奈非那韦水平更高。相比之下，mdr 1a/1b基因敲除小鼠在脑（16.1倍vs. 8.9倍增加）和脾（4.1倍vs. 2.3倍增加）中的奈非那韦水平高于野生小鼠中GF 120918的药理学抑制。最值得注意的是，GF 120918在mdr 1a/1b敲除小鼠中提供了组织特异性作用，在脑（类似于21倍）和心脏（3.3倍）中的药物蓄积增加（p < 0.05）。我们的研究结果表明，mdr 1a/1b非依赖性机制也可能有助于奈非那韦在小鼠体内的组织分布。(C)2005 Wiley-Liss，Inc.和美国药剂师协会
Insufficient concentrations of protease inhibitors such as nelfinavir may reduce the effectiveness of HIV dementia treatment. The efflux transporter mdr1 product P-glycoprotein (P-gp) has been demonstrated to play a role in limiting nelfinavir brain levels. The goal of this study was to compare the effect of GF120918 (10 mg/kg, IV), a P-gp inhibitor, on intravenous nelfinavir (10 mg/kg) in vivo disposition and tissue penetration in P-gp-competent mdr1a/1b (+/+) mice versus P-gp double knockout mdr1a/1b mice. Intravenous administration with the P-gp inhibitor GF120918 to mdr1a/1b mice increased nelfinavir concentrations over a range of 2.3- to 27-fold, whereas nelfinavir distribution in mdr1a/1b (-/-) mice was 2- to 16-fold higher than that in their wild counterparts. Nelfinavir levels after GF120918 coadministration were higher in the heart, liver, and kidneys than those detected with mdr1a/1b knockout mice. In contrast, mdr1a/1b knockout mice exhibited higher nelfinavir levels in the brain (16.1-fold vs. 8.9-fold increase) and spleen (4.1-fold vs. 2.3-fold increase) compared to pharmacological inhibition with GF120918 in wild mice. Most notably, GF120918 provided tissue-specific effects in mdr1a/1b knockout mice with enhanced (p < 0.05) drug accumulation in the brain (similar to 21-fold) and heart (3.3-fold). Our results suggest mdr1a/1b-independant mechanisms may also contribute to nelfinavir tissue distribution in mice. (C) 2005 Wiley-Liss, Inc. and the American Pharmacists Association.