Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

被引：191

作者：

Chu, X. ^{[1
]}

Korzekwa, K. ^{[2
]}

Elsby, R. ^{[3
]}

Fenner, K. ^{[3
]}

Galetin, A. ^{[4
]}

Lai, Y. ^{[5
]}

Matsson, P. ^{[6
]}

Moss, A. ^{[7
]}

Nagar, S. ^{[2
]}

Rosania, G. R. ^{[8
]}

Bai, J. P. F. ^{[9
]}

Polli, J. W. ^{[10
]}

Sugiyama, Y. ^{[11
]}

Brouwer, K. L. R. ^{[12
]}

机构：

[1] Merck & Co Inc, Dept Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA

[2] Temple Univ, Sch Pharm, Dept Pharmaceut Sci, Philadelphia, PA 19122 USA

[3] AstraZeneca R&D Alderley Pk, Global DMPK, Macclesfield, Cheshire, England

[4] Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester, Lancs, England

[5] Pfizer Inc, Pharmacokinet Dynam & Metab, Groton, CT 06340 USA

[6] Uppsala Univ, Dept Pharm, Uppsala Univ Drug Optimizat & Pharmaceut Platform, Uppsala, Sweden

[7] Seattle Genet Inc, Clin Pharmacol, Bothell, WA USA

[8] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[9] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA

[10] GlaxoSmithKline Inc, Drug Metab & Pharmacokinet, Res Triangle Pk, NC USA

[11] RIKEN Res Cluster Innovat, RIKEN Innovat Ctr, Sugiyama Lab, Yokohama, Kanagawa, Japan

[12] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, UNC Eshelman Sch Pharm, Chapel Hill, NC USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2013年 / 94卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PHYSIOLOGICALLY-BASED PHARMACOKINETICS; LIPOPHILIC AMINE DRUGS; HEPATOBILIARY TRANSPORT; EFFLUX TRANSPORTERS; RAT HEPATOCYTES; P-GLYCOPROTEIN; HEPATIC-UPTAKE; CAPILLARY-ELECTROPHORESIS; ABCC2; MRP2; IN-VITRO;

D O I：

10.1038/clpt.2013.78

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.

引用

页码：126 / 141

页数：16

共 75 条

[1] Recent advances in capillary electrophoretic analysis of individual cells [J].

Arcibal, Imee G. ;

Santillo, Michael F. ;

Ewing, Andrew G. .

ANALYTICAL AND BIOANALYTICAL CHEMISTRY, 2007, 387 (01) :51-57

[2] The binding of drugs to hepatocytes and its relationship to physicochemical properties [J].

Austin, RP ;

Barton, P ;

Mohmed, S ;

Riley, RJ .

DRUG METABOLISM AND DISPOSITION, 2005, 33 (03) :419-425

[3] Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction The GEOSTAT-1 Study [J].

Bailey, Kristian M. ;

Romaine, Simon P. R. ;

Jackson, Beryl M. ;

Farrin, Amanda J. ;

Efthymiou, Maria ;

Barth, Julian H. ;

Copeland, Joanne ;

McCormack, Terry ;

Whitehead, Andrew ;

Flather, Marcus D. ;

Samani, Nilesh J. ;

Nixon, Jane ;

Hall, Alistair S. ;

Balmforth, Anthony J. .

CIRCULATION-CARDIOVASCULAR GENETICS, 2010, 3 (03) :276-285

[4] TC-99M-HIDA CHOLESCINTIGRAPHY IN DUBIN-JOHNSON AND ROTOR SYNDROMES [J].

BARMEIR, S ;

BARON, J ;

SELIGSON, U ;

GOTTESFELD, F ;

LEVY, R ;

GILAT, T .

RADIOLOGY, 1982, 142 (03) :743-746

[5] The steady-state Michaelis-Menten analysis of P-glycoprotein mediated transport through a confluent cell monolayer cannot predict the correct Michaelis constant Km [J].

Bentz, J ;

Tran, TT ;

Polli, JW ;

Ayrton, A ;

Ellens, H .

PHARMACEUTICAL RESEARCH, 2005, 22 (10) :1667-1677

[6] Species differences in drug transporters and implications for translating preclinical findings to humans [J].

Chu, Xiaoyan ;

Bleasby, Kelly ;

Evers, Raymond .

EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2013, 9 (03) :237-252

[7] Uptake Rate of Cationic Mitochondrial Inhibitor MKT-077 Determines Cellular Oxygen Consumption Change in Carcinoma Cells [J].

Chunta, John L. ;

Vistisen, Kerry S. ;

Yazdi, Zeinab ;

Braun, Rod D. .

PLOS ONE, 2012, 7 (05)

[8] Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury Is Impaired in FXR-Null Mice [J].

Cui, Yue J. ;

Aleksunes, Lauren M. ;

Tanaka, Yuji ;

Goedken, Michael J. ;

Klaassen, Curtis D. .

TOXICOLOGICAL SCIENCES, 2009, 110 (01) :47-60

[9] In Vitro Inhibition of the Bile Salt Export Pump Correlates with Risk of Cholestatic Drug-Induced Liver Injury in Humans [J].

Dawson, Sarah ;

Stahl, Simone ;

Paul, Nikki ;

Barber, Jane ;

Kenna, J. Gerald .

DRUG METABOLISM AND DISPOSITION, 2012, 40 (01) :130-138

[10] Drug Transporters in Drug Efficacy and Toxicity [J].

DeGorter, M. K. ;

Xia, C. Q. ;

Yang, J. J. ;

Kim, R. B. .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 52, 2012, 52 :249-273

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