title: In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy.
abstract: The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2Areceptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: I
authors.identifier: 0000-0002-1557-4416
authors.initials: I
authors.lastname: Loryan
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Melander
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Svensson
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Payan
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: König
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Jansson
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Hammarlund-Udenaes
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000493:pharmacokinetics; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid; D003024:Clozapine / Q000493:pharmacokinetics; D006220:Haloperidol / Q000493:pharmacokinetics; D008297:Male; D009480:Neuropharmacology; D000077152:Olanzapine; D000068882:Paliperidone Palmitate / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D018967:Risperidone / Q000493:pharmacokinetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D001569:Benzodiazepines; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine; D000068882:Paliperidone Palmitate
references.citation: Adv Pharmacol. 2014;71:45-111
references.pmid: 25307214
references.citation: Pharm Res. 2000 Oct;17(10):1220-7
references.pmid: 11145227
references.citation: Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
references.pmid: 8935801
references.citation: Psychiatry Res. 1988 Jan;23(1):1-10
references.pmid: 3363012
references.citation: Life Sci. 1992;51(6):449-60
references.pmid: 1635423
references.citation: Neurosci Lett. 1998 Sep 11;253(3):201-3
references.pmid: 9792246
references.citation: Psychopharmacology (Berl). 1997 May;131(2):148-52
references.pmid: 9201802
references.citation: J Physiol. 1910 Jul 1;40(5):389-403
references.pmid: 16993015
references.citation: Drug Metab Dispos. 2009 Apr;37(4):753-60
references.pmid: 19158315
references.citation: Cochrane Database Syst Rev. 2013 Nov 18;(11):CD006625
references.pmid: 24249315
references.citation: Anesthesiology. 2008 Mar;108(3):495-505
references.pmid: 18292687
references.citation: J Med Chem. 2009 Oct 22;52(20):6233-43
references.pmid: 19764786
references.citation: Ann Neurol. 2011 Aug;70(2):194-206
references.pmid: 21674586
references.citation: Am J Forensic Med Pathol. 2001 Sep;22(3):270-4
references.pmid: 11563738
references.citation: Fluids Barriers CNS. 2013 Jan 21;10(1):6
references.pmid: 23336814
references.citation: Psychiatry Res. 2010 Aug 30;183(2):151-6
references.pmid: 20620031
references.citation: Basic Clin Pharmacol Toxicol. 2010 Mar;106(3):215-20
references.pmid: 20050843
references.citation: Br J Psychiatry. 2008 Mar;192(3):161-3
references.pmid: 18310570
references.citation: Clin Pharmacol Ther. 2012 Aug;92 (2):221-7
references.pmid: 22713701
references.citation: J Pharmacol Exp Ther. 2007 Oct;323(1):346-55
references.pmid: 17646430
references.citation: Cardiovasc Psychiatry Neurol. 2009;2009:278531
references.pmid: 19936105
references.citation: Drug Metab Dispos. 2005 Jan;33(1):175-81
references.pmid: 15502010
references.citation: Eur J Nucl Med Mol Imaging. 2010 May;37(5):942-53
references.pmid: 20016890
references.citation: Adv Drug Deliv Rev. 2004 Oct 14;56(12):1825-57
references.pmid: 15381336
references.citation: Biopharm Drug Dispos. 2002 Nov;23(8):327-38
references.pmid: 12415573
references.citation: Br J Pharmacol. 2001 Oct;134(4):807-14
references.pmid: 11606321
references.citation: J Pharm Sci. 2007 Apr;96(4):729-46
references.pmid: 17117426
references.citation: Mol Psychiatry. 2002;7(3):317-21
references.pmid: 11920159
references.citation: Drug Metab Dispos. 2009 Jun;37(6):1226-33
references.pmid: 19299522
references.citation: Am J Psychiatry. 2000 Apr;157(4):514-20
references.pmid: 10739409
references.citation: Forensic Sci Int. 2006 Mar 10;157(2-3):121-30
references.pmid: 15936909
references.citation: J Clin Psychopharmacol. 1998 Feb;18(1):82-3
references.pmid: 9472848
references.citation: Drug Metab Dispos. 2009 Jul;37(7):1548-56
references.pmid: 19389861
references.citation: Drug Metab Dispos. 2007 Sep;35(9):1711-9
references.pmid: 17591680
references.citation: Drug Metab Dispos. 2011 Mar;39(3):353-62
references.pmid: 21149540
references.citation: J Vis Exp. 2007;(7):269
references.pmid: 18989440
references.citation: J Pharmacol Exp Ther. 2002 Sep;302(3):1129-34
references.pmid: 12183672
references.citation: Pharm Res. 2014 Aug;31(8):2203-19
references.pmid: 24623476
references.citation: Pharmacopsychiatry. 1998 May;31(3):102-9
references.pmid: 9657237
references.citation: Lancet. 2013 Sep 14;382(9896):951-62
references.pmid: 23810019
references.citation: Eur Arch Psychiatry Clin Neurosci. 2006 Aug;256(5):274-80
references.pmid: 16788768
references.citation: J Neurochem. 1966 Aug;13(8):655-69
references.pmid: 5950056
references.citation: Psychiatry Res. 2014 Jul 30;217(3):143-6
references.pmid: 24745469
references.citation: EJNMMI Res. 2012 Oct 16;2(1):58
references.pmid: 23072492
references.citation: CPT Pharmacometrics Syst Pharmacol. 2015 May;4(5):305-11
references.pmid: 26225256
references.citation: Fluids Barriers CNS. 2014 Nov 14;11(1):25
references.pmid: 25414790
references.citation: J Cereb Blood Flow Metab. 2010 Jan;30(1):150-61
references.pmid: 19756019
references.citation: Mol Pharm. 2015 Feb 2;12(2):520-32
references.pmid: 25496026
references.citation: J Cereb Blood Flow Metab. 2012 Apr;32(4):759-68
references.pmid: 22186667
references.citation: J Cereb Blood Flow Metab. 2010 Mar;30(3):510-5
references.pmid: 20010957
references.citation: Pharm Res. 2008 Aug;25(8):1737-50
references.pmid: 18058202