Etravirine in CSF is highly protein bound

被引：22

作者：

Anh Nguyen ^{[1
]}

Rossi, Steven ^{[1
]}

Croteau, David ^{[2
]}

Best, Brookie M. ^{[1
,3
]}

Clifford, David ^{[4
]}

Collier, Ann C. ^{[5
]}

Gelman, Benjamin ^{[6
]}

Marra, Christina ^{[5
]}

McArthur, Justin ^{[7
]}

McCutchan, J. Allen ^{[8
]}

Morgello, Susan ^{[9
]}

Simpson, David ^{[10
]}

Ellis, Ronald J. ^{[2
]}

Grant, Igor ^{[11
]}

Capparelli, Edmund ^{[1
]}

Letendre, Scott ^{[8
]}

机构：

[1] Univ Calif San Diego, Rady Childrens Hosp, Dept Pediat, San Diego, CA 92123 USA

[2] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92108 USA

[3] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA

[4] Washington Univ, Dept Neurol, St Louis, MO 63110 USA

[5] Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA

[6] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA

[7] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA

[8] Univ Calif San Diego, Dept Med, San Diego, CA 92108 USA

[9] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA

[10] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA

[11] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92108 USA

来源：

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY | 2013年 / 68卷 / 05期

基金：

美国国家卫生研究院;

关键词：

HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF; IMMUNODEFICIENCY-VIRUS TYPE-1; CEREBROSPINAL-FLUID; HIV RNA; LOPINAVIR; EFFICACY; THERAPY; BINDING; EXCEED;

D O I：

10.1093/jac/dks517

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

Etravirine has high affinity for plasma drug-binding proteins, such as albumin and (1)-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL). Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.82000 (plasma) and 0.78200 (CSF) ng/mL. Subjects were mostly middle-aged (median 43 years) white (78) men (89). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96 (IQR 94.5, 97.2) protein bound in plasma and 98.4 (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3 (IQR 3, 5.9) of total and 101 (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens. Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.

引用

页码：1161 / 1168

页数：8

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