Dmd049148 754..762
نویسندگان
چکیده
Elacridar (ELC) and tariquidar (TQD) are generally thought to be nontransported inhibitors of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), but recent data indicate that they may also be substrates of these multidrug transporters (MDTs). The present study was designed to investigate potential transport of ELC and TQD by MDTs at the blood-brain barrier at tracer doses as used in positron emission tomography (PET) studies. We performed PET scans with carbon-11-labeled ELC and TQD before and after MDT inhibition in wild-type and transporterknockout mice as well as in in vitro transport assays in MDToverexpressing cells. Brain entrance of [C]ELC and [C]TQD administered in nanomolar tracer doses was found to be limited by Pgpand Bcrp1-mediated efflux at the mouse blood-brain barrier. At higher, MDT-inhibitory doses, i.e., 15 mg/kg for TQD and 5 mg/kg for ELC, brain activity uptake of [C]ELC at 25 minutes after tracer injection was 5.8 6 0.3, 2.1 6 0.2, and 7.5 6 1.0-fold higher in wild-type, Mdr1a/b, and Bcrp1 mice, respectively, but remained unchanged in Mdr1a/bBcrp1 mice. Activity uptake of [C]TQD was 2.8 6 0.2 and 6.8 6 0.4-fold higher in wild-type and Bcrp1 mice, but remained unchanged in Mdr1a/b and Mdr1a/bBcrp1 mice. Consistent with the in vivo findings, in vitro uptake assays in Pgpand Bcrp1-overexpressing cell lines confirmed low intracellular accumulation of ELC and TQD at nanomolar concentrations and increased uptake at micromolar concentrations. As this study shows that microdoses can behave pharmacokinetically differently fromMDT-inhibitory doses if a compound interacts with MDTs, conclusions from microdose studies should be drawn carefully.
منابع مشابه
College Physics
A aberration, 949 aberrations, 947 absolute pressure, 368, 388 absolute zero, 431, 461 ac current, 711, 722 ac voltage, 711, 722 acceleration, 43, 75, 126, 153 acceleration due to gravity, 62, 75 accommodation, 931, 949 accuracy, 25, 31 acoustic impedance , 615, 620 active transport, 419, 419 activity, 1131, 1140 adaptive optics, 947, 949 adhesive forces, 377, 388 adiabatic, 515 adiabatic proce...
متن کاملA Bibliography of Papers in Lecture Notes in Computer Science ( 1997 ) , Part 1 of 2
((2)) [843]. + [197, 2156]. 1 [205]. 12 [2283]. 2 [1255, 56, 2077, 291, 289, 1207, 1833, 1774, 2245, 290]. 3 [762, 104, 326, 295, 56, 681, 1212, 758, 929, 291, 754, 67, 289, 1742, 757, 305, 1770, 286, 742, 310, 751, 2259, 2295, 2278, 2244, 2289, 1745, 2283, 2286, 2263, 1766, 290]. 4 [56, 283]. 5 [2258]. 6 [2258]. << [2156]. β [959, 870]. χ [1510]. D [799, 1978, 1992, 2219]. E [812]. K [250, 196...
متن کاملMicroRNA-762 Is Upregulated in Human Corneal Epithelial Cells in Response to Tear Fluid and Pseudomonas aeruginosa Antigens and Negatively Regulates the Expression of Host Defense Genes Encoding RNase7 and ST2
Mucosal surfaces regulate defenses against infection and excessive inflammation. We previously showed that human tears upregulated epithelial expression of genes encoding RNase7 and ST2, which inhibited Pseudomonas aeruginosa invasion of human corneal epithelial cells. Here, microRNA microarrays were used to show that a combination of tear fluid exposure (16 h) then P. aeruginosa antigens (3 h)...
متن کاملmiR-762 promotes porcine immature Sertoli cell growth via the ring finger protein 4 (RNF4) gene
A growing number of reports have revealed that microRNAs (miRNAs) play critical roles in spermatogenesis. Our previous study showed that miR-762 is differentially expressed in immature and mature testes of Large White boars. Our present data shows that miR-762 directly binds the 3' untranslated region (3'UTR) of ring finger protein 4 (RNF4) and down-regulates RNF4 expression. A single nucleotid...
متن کامل