Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery

被引：183

作者：

Wasan, Kishor M. ^{[1
]}

Brocks, Dion R. ^{[2
]}

Lee, Stephen D. ^{[1
]}

Sachs-Barrable, Kristina ^{[1
]}

Thornton, Sheila J. ^{[1
]}

机构：

[1] Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC V6T 1Z3, Canada

[2] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada

来源：

NATURE REVIEWS DRUG DISCOVERY | 2008年 / 7卷 / 01期

关键词：

D O I：

10.1038/nrd2353

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

In contrast to many traditional pharmaceutical agents that exhibit a high degree of aqueous solubility, new drug candidates are frequently highly lipophilic compounds. The aqueous environment of the blood provides a thermodynamically unfavourable environment for the disposition of such hydrophobic drugs. However, this limitation can be overcome by association with circulating lipoproteins. Elucidation of the mechanisms that dictate drug-lipoprotein association and blood-to-tissue partitioning of lipoprotein encapsulated drugs might yield valuable insight into the factors governing the pharmacological activity and potential toxicity of these compounds. This Review discusses the impact of hydrophobic drug-lipoprotein interactions on pharmacokinetics, drug metabolism, tissue distribution and biological activity of various hydrophobic compounds, and outlines how best to use this information in drug discovery and development programmes.

引用

页码：84 / 99

页数：16

共 199 条

[31] INDUCTION OF MID-TERM ABORTION BY TRICHOSANTHIN IN LABORATORY-ANIMALS [J].

CHANG, MC ;

SAKSENA, SK ;

LAU, IF ;

WANG, YH .

CONTRACEPTION, 1979, 19 (02) :175-184

[32]

CHAO Y, 1979, J BIOL CHEM, V254, P1360

[33] Mechanism of prebeta-HDL formation and activation [J].

Chau, PL ;

Nakamura, Y ;

Fielding, CJ ;

Fielding, PE .

BIOCHEMISTRY, 2006, 45 (12) :3981-3987

[34] Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: Incidence, risk factors, progression, and prognosis [J].

Chueh, SCJ ;

Kahan, BD .

TRANSPLANTATION, 2003, 76 (02) :375-382

[35] Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake [J].

Chung, NS ;

Wasan, KM .

ADVANCED DRUG DELIVERY REVIEWS, 2004, 56 (09) :1315-1334

[36] CYCLOSPORINE, LOW-DENSITY LIPOPROTEIN, AND CHOLESTEROL [J].

DEGROEN, PC .

MAYO CLINIC PROCEEDINGS, 1988, 63 (10) :1012-1021

[37] CENTRAL-NERVOUS-SYSTEM TOXICITY AFTER LIVER-TRANSPLANTATION - THE ROLE OF CYCLOSPORINE AND CHOLESTEROL [J].

DEGROEN, PC ;

AKSAMIT, AJ ;

RAKELA, J ;

FORBES, GS ;

KROM, RAF .

NEW ENGLAND JOURNAL OF MEDICINE, 1987, 317 (14) :861-866

[38] CYCLOSPORINE LEUKOENCEPHALOPATHY INDUCED BY INTRAVENOUS LIPID SOLUTION [J].

DEKLIPPEL, N ;

SENNESAEL, J ;

LAMOTE, J ;

EBINGER, G ;

DEKEYSER, J .

LANCET, 1992, 339 (8801) :1114-1114

[39] Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport [J].

Duffy, D ;

Rader, DJ .

CIRCULATION, 2006, 113 (08) :1140-1150

[40] Molecular mechanism of the blockade of plasma cholesteryl ester transfer protein by its physiological inhibitor apolipoprotein CI [J].

Dumont, L ;

Gautier, T ;

de Barros, JPP ;

Laplanche, H ;

Blache, D ;

Ducoroy, P ;

Fruchart, J ;

Fruchart, JC ;

Gambert, P ;

Masson, D ;

Lagrost, L .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (45) :38108-38116

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