Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport

被引:102
作者
Jones, K
Hoggard, PG
Sales, SD
Khoo, S
Davey, R
Back, DJ
机构
[1] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside, England
[2] Royal N Shore Hosp, Dept Clin Oncol, St Leonards, NSW 2065, Australia
关键词
protease inhibitors; antiretroviral therapy; accumulation; P-glycoprotein; multidrug resistance-associated protein;
D O I
10.1097/00002030-200104130-00002
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objectives: To investigate the intracellular accumulation of HIV protease inhibitors (PI) and to assess the effect of active transport on this accumulation. Methods: CEM cells were incubated with a PI for 18 h and the intracellular concentration determined using cell number and radioactivity. The effect of active transport was investigated using cells expressing P-glycoprotein (CEMVBL) and cells expressing multidrug resistance-associated protein 1 (MRP1; CEME1000) Incubations were also carried out at 4 degreesC and in the presence of 2-deoxyglucose plus rotenone to examine the effect of inhibiting active transport. Results: Nelfinavir (NFV) accumulated to the greatest extent (> 80-fold) followed by saquinavir (SQV; similar to 30-fold), ritonavir (RTV; 3-7-fold) and finally indinavir (IDV; extracellular equivalent to intracellular). In CEMVBL cells there was a significant reduction in the intracellular accumulation of NFV, SQV and RTV and in CEME1000 cells there was reduced accumulation of SQV and RTV Inhibition of active transport processes caused a reduction in SQV and RTV accumulation but had no effect on IDV accumulation in all cell types. NFV accumulation was increased in CEM(VBL)cells as a result of inhibition of active transport. Conclusions: Marked differences can be detected in the intracellular accumulation of HIV PI drugs in vitro. Both P-glycoprotein and MRP1 may play a role in limiting the intracellular concentration of the PI and active influx mechanisms may contribute to drug accumulation. (C) 2001 Lippincott Williams & Wilkins.
引用
收藏
页码:675 / 681
页数:7
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