PMID- 26202880 OWN - NLM STAT- MEDLINE DCOM- 20160621 LR - 20220129 IS - 1543-8392 (Electronic) IS - 1543-8384 (Print) IS - 1543-8384 (Linking) VI - 12 IP - 9 DP - 2015 Sep 8 TI - Factors Governing P-Glycoprotein-Mediated Drug-Drug Interactions at the Blood-Brain Barrier Measured with Positron Emission Tomography. PG - 3214-25 LID - 10.1021/acs.molpharmaceut.5b00168 [doi] AB - The adenosine triphosphate-binding cassette transporter P-glycoprotein (ABCB1/Abcb1a) restricts at the blood-brain barrier (BBB) brain distribution of many drugs. ABCB1 may be involved in drug-drug interactions (DDIs) at the BBB, which may lead to changes in brain distribution and central nervous system side effects of drugs. Positron emission tomography (PET) with the ABCB1 substrates (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide and the ABCB1 inhibitor tariquidar has allowed direct comparison of ABCB1-mediated DDIs at the rodent and human BBB. In this work we evaluated different factors which could influence the magnitude of the interaction between tariquidar and (R)-[(11)C]verapamil or [(11)C]-N-desmethyl-loperamide at the BBB and thereby contribute to previously observed species differences between rodents and humans. We performed in vitro transport experiments with [(3)H]verapamil and [(3)H]-N-desmethyl-loperamide in ABCB1 and Abcb1a overexpressing cell lines. Moreover we conducted in vivo PET experiments and biodistribution studies with (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide in wild-type mice without and with tariquidar pretreatment and in homozygous Abcb1a/1b((-/-)) and heterozygous Abcb1a/1b((+/-)) mice. We found no differences for in vitro transport of [(3)H]verapamil and [(3)H]-N-desmethyl-loperamide by ABCB1 and Abcb1a and its inhibition by tariquidar. [(3)H]-N-Desmethyl-loperamide was transported with a 5 to 9 times higher transport ratio than [(3)H]verapamil in ABCB1- and Abcb1a-transfected cells. In vivo, brain radioactivity concentrations were lower for [(11)C]-N-desmethyl-loperamide than for (R)-[(11)C]verapamil. Both radiotracers showed tariquidar dose dependent increases in brain distribution with tariquidar half-maximum inhibitory concentrations (IC50) of 1052 nM (95% confidence interval CI: 930-1189) for (R)-[(11)C]verapamil and 1329 nM (95% CI: 980-1801) for [(11)C]-N-desmethyl-loperamide. In homozygous Abcb1a/1b((-/-)) mice brain radioactivity distribution was increased by 3.9- and 2.8-fold and in heterozygous Abcb1a/1b((+/-)) mice by 1.5- and 1.1-fold, for (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide, respectively, as compared with wild-type mice. For both radiotracers radiolabeled metabolites were detected in plasma and brain. When brain and plasma radioactivity concentrations were corrected for radiolabeled metabolites, brain distribution of (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide was increased in tariquidar (15 mg/kg) treated animals by 14.1- and 18.3-fold, respectively, as compared with vehicle group. Isoflurane anesthesia altered [(11)C]-N-desmethyl-loperamide but not (R)-[(11)C]verapamil metabolism, and this had a direct effect on the magnitude of the increase in brain distribution following ABCB1 inhibition. Our data furthermore suggest that in the absence of ABCB1 function brain distribution of [(11)C]-N-desmethyl-loperamide but not (R)-[(11)C]verapamil may depend on cerebral blood flow. In conclusion, we have identified a number of important factors, i.e., substrate affinity to ABCB1, brain uptake of radiolabeled metabolites, anesthesia, and cerebral blood flow, which can directly influence the magnitude of ABCB1-mediated DDIs at the BBB and should therefore be taken into consideration when interpreting PET results. FAU - Wanek, Thomas AU - Wanek T AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. FAU - Romermann, Kerstin AU - Romermann K AD - Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine Hannover , Hannover, Germany. AD - Department of Clinical Pharmacology, Medical University of Vienna , Vienna, Austria. FAU - Mairinger, Severin AU - Mairinger S AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. FAU - Stanek, Johann AU - Stanek J AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. AD - Department of Clinical Pharmacology, Medical University of Vienna , Vienna, Austria. FAU - Sauberer, Michael AU - Sauberer M AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. FAU - Filip, Thomas AU - Filip T AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. FAU - Traxl, Alexander AU - Traxl A AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. FAU - Kuntner, Claudia AU - Kuntner C AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. FAU - Pahnke, Jens AU - Pahnke J AD - Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS) , Oslo, Norway. AD - Lubeck Institute of Experimental Dermatology, University of Lubeck , Lubeck, Germany. FAU - Bauer, Florian AU - Bauer F AD - Department of Medicinal Chemistry, University of Vienna , Vienna, Austria. FAU - Erker, Thomas AU - Erker T AD - Department of Medicinal Chemistry, University of Vienna , Vienna, Austria. FAU - Loscher, Wolfgang AU - Loscher W AD - Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine Hannover , Hannover, Germany. FAU - Muller, Markus AU - Muller M AD - Department of Clinical Pharmacology, Medical University of Vienna , Vienna, Austria. FAU - Langer, Oliver AU - Langer O AD - Health & Environment Department, AIT Austrian Institute of Technology GmbH , Seibersdorf, Austria. AD - Department of Clinical Pharmacology, Medical University of Vienna , Vienna, Austria. LA - eng GR - F 3513/FWF_/Austrian Science Fund FWF/Austria GR - I 1609/FWF_/Austrian Science Fund FWF/Austria GR - P 24894/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150803 PL - United States TA - Mol Pharm JT - Molecular pharmaceutics JID - 101197791 RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Calcium Channel Blockers) RN - 0 (Carbon Radioisotopes) RN - 0 (Radiopharmaceuticals) RN - 0R07BFN7L3 (N-demethylloperamide) RN - 6X9OC3H4II (Loperamide) RN - CJ0O37KU29 (Verapamil) SB - IM MH - ATP Binding Cassette Transporter, Subfamily B/metabolism MH - ATP-Binding Cassette Transporters/*metabolism MH - Animals MH - Biological Transport/drug effects MH - Blood-Brain Barrier/diagnostic imaging/*metabolism MH - Brain/diagnostic imaging/*metabolism MH - Calcium Channel Blockers/metabolism MH - Carbon Radioisotopes/metabolism MH - Drug Interactions MH - Female MH - Humans MH - Loperamide/*analogs & derivatives/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Positron-Emission Tomography/*methods MH - Radiopharmaceuticals/*metabolism MH - Verapamil/*metabolism PMC - PMC4566129 OTO - NOTNLM OT - (R)-[11C]verapamil OT - P-glycoprotein OT - [11C]-N-desmethyl-loperamide OT - blood-brain barrier OT - drug-drug interaction OT - positron emission tomography OT - tariquidar EDAT- 2015/07/24 06:00 MHDA- 2016/06/22 06:00 PMCR- 2015/09/11 CRDT- 2015/07/24 06:00 PHST- 2015/07/24 06:00 [entrez] PHST- 2015/07/24 06:00 [pubmed] PHST- 2016/06/22 06:00 [medline] PHST- 2015/09/11 00:00 [pmc-release] AID - 10.1021/acs.molpharmaceut.5b00168 [doi] PST - ppublish SO - Mol Pharm. 2015 Sep 8;12(9):3214-25. doi: 10.1021/acs.molpharmaceut.5b00168. Epub 2015 Aug 3.