P-Glycoprotein (ABCB1) Transports the Primary Active Tamoxifen Metabolites Endoxifen and 4-Hydroxytamoxifen and Restricts Their Brain Penetration

被引:59
作者
Iusuf, Dilek [1 ]
Teunissen, Sebastiaan F. [2 ]
Wagenaar, Els [1 ]
Rosing, Hilde [2 ]
Beijnen, Jos H. [2 ]
Schinkel, Alfred H. [1 ]
机构
[1] Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands
[2] Slotervaart Hosp, Dept Pharm & Pharmacol, Amsterdam, Netherlands
关键词
BREAST-CANCER-CELLS; MULTIDRUG-RESISTANCE; MAIN METABOLITES; DRUG; BARRIER; CYP2D6; EXPRESSION; METASTASES; THERAPY; PHARMACOKINETICS;
D O I
10.1124/jpet.110.178301
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
P-glycoprotein (P-gp, ABCB1) is a highly efficient drug efflux pump expressed in brain, liver, and small intestine, but also in tumor cells, that affects pharmacokinetics and confers therapy resistance for many anticancer drugs. The aim of this study was to investigate the impact of P-gp on tamoxifen and its primary active metabolites, 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen. We used in vitro transport assays and Abcb1a/1b(-/-) mice to investigate the impact of P-gp on the oral availability and brain penetration of tamoxifen and its metabolites. Systemic exposure of tamoxifen and its metabolites after oral administration of tamoxifen (50 mg/kg) was not changed in the absence of P-gp. However, brain accumulation of tamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were modestly, but significantly (1.5- to 2-fold), increased. Endoxifen, however, displayed a 9-fold higher brain penetration at 4 h after administration. Endoxifen was transported by P-gp in vitro. Upon direct oral administration of endoxifen (20 mg/kg), systemic exposure was slightly decreased in Abcb1a/1b(-/-) mice, but brain accumulation of endoxifen was dramatically increased (up to 23-fold at 4 h after administration). Shortly after high-dose intravenous administration (5 or 20 mg/kg), endoxifen brain accumulation was increased only 2-fold in Abcb1a/1b(-/-) mice compared with wild-type mice, suggesting a partial saturation of P-gp at the blood-brain barrier. Endoxifen, the clinically most relevant metabolite of tamoxifen, is a P-gp substrate in vitro and in vivo, where P-gp limits its brain penetration. P-gp might thus be relevant for tamoxifen/endoxifen resistance of P-gp-positive breast cancer and tumors positioned behind a functional blood-brain barrier.
引用
收藏
页码:710 / 717
页数:8
相关论文
共 41 条
[1]   Endoxifen, a New Cornerstone of Breast Cancer Therapy: Demonstration of Safety,Tolerability, and Systemic Bioavailability in Healthy Human Subjects [J].
Ahmad, A. ;
Shahabuddin, S. ;
Sheikh, S. ;
Kale, P. ;
Krishnappa, M. ;
Rane, R. C. ;
Ahmad, I. .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2010, 88 (06) :814-817
[2]   Orally administered Endoxifen is a new therapeutic agent for breast cancer [J].
Ahmad, Ateeq ;
Ali, Shoukath M. ;
Ahmad, Moghis U. ;
Sheikh, Saifuddin ;
Ahmad, Imran .
BREAST CANCER RESEARCH AND TREATMENT, 2010, 122 (02) :579-584
[3]   Endoxifen is a new potent inhibitor of PKC: A potential therapeutic agent for bipolar disorder [J].
Ali, Shoukath M. ;
Ahmad, Ateeq ;
Shahabuddin, Syed ;
Ahmad, Moghis U. ;
Sheikh, Saifuddin ;
Ahmad, Imran .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (08) :2665-2667
[4]   Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A [J].
Bekaii-Saab, TS ;
Perloff, MD ;
Weemhoff, JL ;
Greenblatt, DJ ;
von Moltke, LL .
BIOPHARMACEUTICS & DRUG DISPOSITION, 2004, 25 (07) :283-289
[5]   Mammalian ABC transporters in health and disease [J].
Borst, P ;
Elferink, RO .
ANNUAL REVIEW OF BIOCHEMISTRY, 2002, 71 :537-592
[6]   INTERACTION OF TAMOXIFEN WITH THE MULTIDRUG-RESISTANCE P-GLYCOPROTEIN [J].
CALLAGHAN, R ;
HIGGINS, CF .
BRITISH JOURNAL OF CANCER, 1995, 71 (02) :294-299
[7]   Multidrug resistance/P-glycoprotein and breast cancer: Review and meta-analysis [J].
Clarke, R ;
Leonessa, F ;
Trock, B .
SEMINARS IN ONCOLOGY, 2005, 32 (06) :S9-S15
[8]   Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux [J].
Dai, HQ ;
Marbach, P ;
Lemaire, M ;
Hayes, M ;
Elmquist, WF .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 304 (03) :1085-1092
[9]  
Dantzig AH, 1996, CANCER RES, V56, P4171
[10]  
Evers R, 1998, J CLIN INVEST, V101, P1310, DOI 10.1172/JCI119886