(R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function:: in vitro and in vivo evaluation

被引:96
作者
Luurtsema, G [1 ]
Molthoff, CFM
Windhorst, AD
Smit, JW
Keizer, H
Boellaard, R
Lammertsma, AA
Franssen, EJF
机构
[1] VU Univ, Med Ctr, PET Ctr, Amsterdam, Netherlands
[2] VU Univ, Med Ctr, Dept Pharm, Amsterdam, Netherlands
[3] Radionuclide Ctr VU, Amsterdam, Netherlands
[4] Netherlands Canc Inst, Amsterdam, Netherlands
[5] Solvay Pharmaceut, Weesp, Netherlands
关键词
C-11; verapamil; BBB; P-gp; enantiomers;
D O I
10.1016/S0969-8051(03)00078-7
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [C-11]verapamil has been used to image P-gp expression in vivo. A racemic tracer, however, is not suitable for quantification. The purpose of the present study was to identify the most appropriate enantiomer of [C-11]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[C-11]verapamil, were synthesized and studied in vivo. For the in vivo model mdr1a/1b double gene knock-out and wild type mice were used. The in vitro study made use of the LLC-PK1 MDR cell line to examine the P-gp mediated transport of both enantiomers. The biodistribution of (R)- and (S)-[C-11]verapamil in dKO and WT mice demonstrated no stereo selectivity of verapamil for P-gp in the blood-brain barrier and in the testes. In addition, no significant differences in P-gp transport for both enantiomers were observed in the in vitro experiments. Previous studies have shown that (R)-verapamil is metabolized less in man and that it has lower affinity for calcium channels. Since (R)and (S)-verapamil have equal transport for P-gp, the (R)-enantiomer seems to be the best and safest candidate as PET-tracer for measuring P-gp function in vivo. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:747 / 751
页数:5
相关论文
共 33 条
[1]  
Bhatti MM, 1997, BIOPHARM DRUG DISPOS, V18, P387, DOI 10.1002/(SICI)1099-081X(199707)18:5<387::AID-BDD26>3.0.CO
[2]  
2-X
[3]   Characterization of a single LSO crystal layer high resolution research tomograph [J].
Boellaard, R ;
Buijs, F ;
de Jong, HWAM ;
Lenox, M ;
Gremillion, T ;
Lammertsma, AA .
PHYSICS IN MEDICINE AND BIOLOGY, 2003, 48 (04) :429-448
[4]   Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting - Implications of the barriers between blood and brain [J].
de Lange, ECM ;
Danhof, M .
CLINICAL PHARMACOKINETICS, 2002, 41 (10) :691-703
[5]   Synthesis and evaluation of radiolabeled antagonists for imaging of β-adrenoceptors in the brain with PET [J].
Doze, P ;
Elsinga, PH ;
Maas, B ;
Van Waarde, A ;
Wegman, T ;
Vaalburg, W .
NEUROCHEMISTRY INTERNATIONAL, 2002, 40 (02) :145-155
[6]   EFFECTS OF D,1-VERAPAMIL ON ATRIOVENTRICULAR-CONDUCTION IN RELATION TO ITS STEREOSELECTIVE 1ST-PASS METABOLISM [J].
ECHIZEN, H ;
VOGELGESANG, B ;
EICHELBAUM, M .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1985, 38 (01) :71-76
[7]   THE EFFECT OF DEXTRO-VERAPAMIL, LEVO-VEAPAMIL, AND RACEMIC VERAPAMIL ON ATRIOVENTRICULAR-CONDUCTION IN HUMANS [J].
ECHIZEN, H ;
BRECHT, T ;
NIEDERGESASS, S ;
VOGELGESANG, B ;
EICHELBAUM, M .
AMERICAN HEART JOURNAL, 1985, 109 (02) :210-217
[8]   PHARMACOKINETICS OF (+)-VERAPAMIL, (-)-VERAPAMIL AND (+/-)-VERAPAMIL AFTER INTRAVENOUS ADMINISTRATION [J].
EICHELBAUM, M ;
MIKUS, G ;
VOGELGESANG, B .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 17 (04) :453-458
[9]  
Elsinga PH, 1996, J NUCL MED, V37, P1571
[10]   R-(+)-verapamil, S-(-)-verapamil, and racemic verapamil inhibit human retinal pigment epithelial cell contraction [J].
Faude, F ;
Enzmann, V ;
Pöschmann, E ;
Hoffmann, S ;
Wiedemann, P .
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 2000, 238 (06) :537-541