Figure S1. Chemical space of training set and its applicability for
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Teicoplanin Figure S1. Chemical space of training set and its applicability for prediction of the test set. The grey sphere shows the 95% confidence interval of the chemical variation of the training set explained by the first three principal components, which together explain 66% of the chemical variation of the training set. The test set was found to be well spread throughout the chemical space covered by the training set (shown as the red spheres), except for the outlier teicoplanin, an antibacterial mycin. 1 Table SI. Compounds included in the test set. High CNS exposure (CNS exp class 1) is defined as brain to plasma ratio of ≥0.3. All compounds with a brain to plasma ratio <0.3 are sorted in the low CNS exposure class (CNS exp class -1). Compound 1 2 3 4 Acamprosate Acarbose Acrivastine Acyclovir CNS exp class -1 -1 -1 -1 Species/ model mouse, rabbit rat, dog rat rat 5 Adefovir dipivoxil -1 6 7 Alfentanil Almotriptan -1 -1 8 9 10 Ambenonium Amoxicillin Amprenavir -1 -1 -1 11 Atenolol -1 12 13 14 15 Atorvastatin Atovaquone Azathioprine Azithromycin -1 -1 -1 -1 mouse mouse 16 Baclofen -1 rat 17 Benazepril -1 18 19 20 Benserazide Bicalutamide Biotin -1 -1 -1 rat, dog, baboon rat rat rat 21 22 23 Bromocriptine Cabergoline Captopril -1 -1 -1 mouse rat rat BBMEC rat, dog, monkey mouse rat guinea pig human mouse rat rat Support for classification Reference Brain to plasma ratio of 0.03 (mouse) and 0.16 (rabbit) Conclude that the BBB permeability was very low Brain to plasma ratio 0.07 Brain to plasma ratio for three rats low but highly variable (~0.05, 0.2 and 0.5) BBB permeability determined to be low Conclude poor penetration to CNS Courtyn et al., Nuclear Med Biol 2004 Ahr et al., Arzneimittelforschung 1989 Mahar Doan et al., Pharmacology 1994 Ståhle &Oberg, Antimicrob Agents Chemother 1992 Shah et al, Pharm Res 1989 Brain to plasma ratio of 0.19 Conclude low distribution to brain Conclude low distribution to brain Statement: does not permeate the BBB Brain to plasma ratio of 0.14 (PB model) Brain to plasma ratio of 0.07 Brain to plasma ratio of 0.08 Brain to plasma ratio of 0.16 Brain to plasma ratio of 0.07 Brain to plasma ratio of 0.04 Brain to sera ratio of 0.06 Statement: Very small amounts reach the brain Statement: Does not distribute to CNS Kalvass et al., Drug Metab Dispos 2005 Aubets et al., Xenobiotica 2006 Gras et al, Arzneimittelforschung 2001 Bolognesi et al., Il Farmaci, 2003 Tod et al., Pharm Res 2008 Kalvass et al., Drug Metab Dispos 2005 Edwards et al., Antimicrob Agents Chemother 2002 Hakkarainen et al., Int J Pharm 2010 Fridén et al., J Med Chem 2009 Chen et al, Drug Metab Dispos 2007 Dunay et al., Antimicrob Agents Chemother 2004 Therapeutic Drugs (1991), editor C. Dollery, Churchill Livingstone Goodman and Gilman’s The Pharmacological Basis of Therapeutics (10th ed), Eds Hardman and Limbird, McGrowthHall Medical Publishing 2001 Hakkarainen et al., Int J Pharm 2010 Fridén at el., J Med Chem 2009 Waldmeier & Schmid, Arzneimittelforschung 1984 Brain to plasma ratio of 0.08 Brain to plasma ratio of 0.03 Statement: Passage of the BBB occur to a minimal extent Brain to plasma ratio of 0.01 Brain to plasma ratio <0.3 Brain to plasma ratio<0.3 in spite of using brain targeting vehicle Brain to plasma ratio ~0.2 Brain to plasma ratio 0.03 Statement: Not detected in brain http://mt.china-papers.com/2/?p=114528 Schwartz et al., Eur J Clin Pharmacol 1974 Freeman et al., Br J Cancer 1989 Kang & Pardridge, J Pharmacol Exp Therapeut 1994 Vautier et al., Eur J Pharm Sci 2006 Sharma et al., AAPS Pharm Tech 2009 Migdalof et al., Drug Met Rev 1984 2 24 25 26 Carbidopa Cefalexin Cefdinir -1 -1 -1 mouse rat 27 28 Ceftriaxone Cefuroxime -1 -1 rat rat 29 Cephaloridine -1 Brain to plasma ratio <0.01 AUCbrain/AUCplasma of 0.04 Statement: Distributes to CSF in meningitis Statement: Does not cross the BBB 30 Cetirizine -1 mouse guinea pig 31 32 33 34 35 36 37 Cimetidine Clindamycin Delaviridine Desloratadine Diclofenac Diflunisal Dihydrostreptomycin -1 -1 -1 -1 -1 -1 -1 38 39 Dipyridamole Doxorubicin -1 -1 Brain to plasma ratio 0.02 Brain to plasma ratio 0.22 Brain to blood ratio of 0.04 Statement: Does not permeate a normal BBB Brain to plasma ratio of 0.03 Statement: Restricted distribution to CNS Brain to plasma ratio 0.02 Brain to plasma ratio 0.05 Statements: Very poor membrane permeability, Vd equals V of extracellular fluid and very poor CSF distribution Statement: Does not permeate BBB Statement: Does not permeate BBB 40 41 42 43 Doxycycline Enalaprilate Ergocalciferol Ergotamine -1 -1 -1 -1 44 45 Erythromycin Ethambutol -1 -1 46 47 48 Etinylestradiol Etidronate Etoposide -1 -1 -1 rat mouse mouse human 49 50 Felbamate Fexofenadine -1 -1 rat rat rat mouse rat rat rat Statement: Does not permeate the BBB Statement: Not detected in brain Statement: Does not distribute to brain Statement: Insignificant fraction crosses BBB Statement: Does not permeate BBB Statement: Low distribution to brain Statement: Penetration of the BBB has been questioned or denied Statement: Non significant permeation through BBB Not detectable in CSF of healthy patients Statement: Low BBB permeation Brain to plasma ratio of 0.14 Statement: Minimal concentration in brain Low levels found in brain Not detectable in CSF Brain to plasma ratio of 0.1 Brain to plasma ratio of 0.02 FASS – the Swedish PDR (www.fass.se) Klimova Antiobiotiki 1979 NDA downloaded from FDA: http://www.accessdata.fda.gov/drugsatfda_docs/ nda/97/050739s000_050749s000_Omnicef_pharmr.pdf Tsai et al., J Chroatogra B Biomed Sci Appl 1999 FASS – the Swedish PDR (www.fass.se) Lecture Notes on Clinical Pharmacology, Authors Reid, Rubin, Whiting. Oxford: Blackwell Science 2001 Chen et al, Drug Metab Dispos 2003 Gupta et al., Drug Metab Dispos 2006 Salminen et al., J Pharm Biomed Anal 1997 FASS – the Swedish PDR (www.fass.se) Fridén et al., J Med Chem 2009 FASS – the Swedish PDR (www.fass.se) Summerfield et al, J Pharmacol Exp Therapeut 2006 Grace et al., Inflammapharmacol 2000 http://www.inchem.org/documents/jecfa/jecmono/v34je03.ht m Product specifications Goodman and Gilman’s The Pharmacological Basis of Therapeutics (10th ed), Eds Hardman and Limbird, McGrowthHall Medical Publishing 2001 Michel et al., J drug Net Pharmacokinet 1984 Product specifications Cruickshank et al, Biochem J 1954 Evers et al., Psychopharmacol 1999 FASS – the Swedish PDR (www.fass.se) Barling & Selkon, Antimicrob Chemother 1978 http://www.medsafe.govt.nz/profs/datasheet/a/ apoethambutoltab.pdf Berry et al., Drug Metab Dispos 2010 Mönkkönen et al., Pharmacol Toxicol 1989 Broggini et al., Cancer Treat Rep 1983 D’Incalci et al., Cancer Chemother Pharmacol 1982 Potschka et al., Epilepsia 2003 Mahar Doan et al., Pharmacology 1994 3 51 52 Fluorouracil Fluvastatin -1 -1 rat rat 53 Fosamprenavir -1 54 55 56 57 58 59 60 61 62 63 64 65 66 67 Furosemide Fusidic acid Ganciclovir Glimepiride Glipizide Glucosamine Halofuginone Hydrochlorothiazide Hydroxycarbamide Indinavir Indomethacin Itraconazole Ivermectin Ketoconazole -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 rat 68 69 Ketoprofen Levodopa -1 -1 mouse monkey 70 71 Levofloxacin Lopinavir -1 -1 rat 72 73 74 75 76 77 78 79 80 81 82 Lufenuron M3G M6G Melphalan Mepenzolate 6-Mercaptopurine Mesalazine Methotrexate Methyldopa Metronidazole Mizolastine -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 rat mouse rat mouse guinea pig mouse rat mouse mouse mouse rat rat rat rat rat rat Brain to plasma ratio ~0.12 Not detectable in brain, low but detectable concentration after perfusion Statement: Poor penetration of BBB Brain to plasma ratio of 0.03 Statement: Does not permeate BBB Brain to plasma ratio of 0.06 Statement: Low passage over BBB Not distributed to brain Low concentration in brain Not detected in brain Statement: Does not permeate BBB Brain to plasma ratio <0.1 Brain to plasma ratio of 0.08 Brain to plasma ratio of 0.01 AUCbrain/AUCplasma of 0.16 Brain to plasma ratio ~0.03 Brain to plasma ratio of 0.20 Statement: Does not cross intact BBB AUCbrain/AUCplasma of 0.02 Brain to plasma of 0.02. Even if adjusted for metabolism to dopamine, brain to plasma ratio <0.3 Brain to plasma ratio of 0.17 Poor penetration of BBB Relative low concentrations measured in brain Brain to plasma ratio of 0.007 Brain to plasma ratio of 0.008 Limited penetration of BBB Does not permeate BBB Brain to plasma ratio of 0.17 Does not permeate BBB Brain to plasma ratio of 0.004 Brain to plasma ratio <0.3 AUCbrain/AUCblood of 0.23 Does not permeate BBB Sakane et al., J Drug Target 1999 Guillot et al., J Cardiovasc Pharmacol 1993 Goodman and Gilman’s The Pharmacological Basis of Therapeutics (10th ed), Eds Hardman and Limbird, McGrowthHall Medical Publishing 2001 Seno et al, J Pharm Sci 1969 FASS – the Swedish PDR (www.fass.se) Brewster et al., Antimicrob Agents Chemother 1994 FASS – the Swedish PDR (www.fass.se) Goldaniga et al., Arzneimittelforschung 1973 Thorell et al., Appl Rad Isotop 1993 Stecklair et al., Cancer Chemother Pharmacol 2001 Product specifications Dogruel et al., J Neurochem 2003 Kalvass et al., Drug Metab Dispos 2005 Fridén et al., J Med Chem 2009 Imbert et al., Drug Metab Dispos 2003 Kiki-Mvouaka et al, Drug Metab Dispos 2010 Choo et al., Drug Metab Dispos 2000 Daneshmend & Warnock, Clin Pharmacokin 1988 Deguchi et al., J Drug Target 2000 Nomoto et al., Parkinsonism Relat Disord 2009 Fridén et al., J Med Chem 2009 Goodman and Gilman’s The Pharmacological Basis of Therapeutics (10th ed), Eds Hardman and Limbird, McGrowthHall Medical Publishing 2001 http://www.efsa.europa.eu/en/scdocs/doc/189r.pdf Fridén et al., J Med Chem 2009 Fridén et al., J Med Chem 2009 FASS – the Swedish PDR (www.fass.se) http://www.drugs.com/mmx/mepenzolate-bromide.html Deguchi et al., Life Sci 2000 Product specifications Fridén et al., J Med Chem 2009 Opezzo et al., Pharmacol Res 2000 Tsai and Chen, J Chromatogr A 2003 Product specifications 4 83 84 85 86 87 88 89 90 91 92 93 Moxalactam Moxidectin Nadolol Nelfinavir Nicotinic acid Nitrofurantoin Norfloxacin Orlistat Oxytetracycline Paclitaxel PenicillinV -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 rat 94 95 96 97 Phytomenadione Pivmecillinam Pyridostigmine Raloxifene -1 -1 -1 -1 rat dog mouse 98 99 100 Ranitidine Retinol Rifampicin -1 -1 -1 101 102 103 104 105 106 107 Rifapentine Ritonavir Rizatriptan Rosiglitazone Rosuvastatin Salicylic acid Streptomycin -1 -1 -1 -1 -1 -1 -1 108 109 110 111 112 Sulfamethoxazole Sulphasalazine Sulpiride Sumatriptan Teicoplanin -1 -1 -1 -1 -1 113 Telithromycin -1 114 Thiamine -1 rat rat rat rat rat dog rat rat mouse rat rabbit mouse mouse mouse rat rat monkey rat mouse mouse rat Brain to plasma ratio of 0.003 Does not permeate BBB Brain to plasma ratio of 0.11 Brain to plasma ratio of 0.04 Brain to plasma ratio of ~0.02 Brain to plasma ratio of 0.008 Brain to plasma ratio of 0.07 Minimal membrane permeability No detectable concentration in brain Brain to plasma ratio of 0.28 Low distribution to brain and CSF, in meningitis CSF can reach ~5%. Low distribution to brain Brain to sera ratio of 0.02 Statement: Does not permeate normal BBB Does not permeate BBB Brain to blood ratio of 0.06 Brain to plasma ratio <0.05 Brain to plasma ratio of <0.01 Brain to plasma ratio of 0.03 Brain to plasma ratio of 0.18 Brain to plasma ratio of 0.04 Brain to plasma ratio of 0.20 Brain to plasma ratio of 0.05 Very low uptake in brain Brain to plasma ratio of 0.05 Very poor membrane permeation, low Vd and very poor distribution to CSF Brain to plasma ratio <0.3 Brain to plasma ratio of 0.005 Brain to plasma ratio of 0.08 Brain to plasma ratio of 0.13 Slow diffusion to CSF, no therapeutic concentrations are obtained Poor passage through BBB Brain to perfusate ratio of 0.02 (frontal cortex) Fridén et al., J Med Chem 2009 Product specifications Fridén et al., J Med Chem 2009 Fridén et al., J Med Chem 2009 Kang et al., J Pharmacobio-Dyn 1990 Fridén et al., J Med Chem 2009 Fridén et al., J Med Chem 2009 Ballinger, Exp Opinion Pharmacother 2000. Barza et al., Antimicrob Agents Chemother 1975 Fridén et al., J Med Chem 2009 Product specifications Thijssen & Drittij-Reijnders, Br J Nutrition 1994 Roholt, Antimicrob Chemother 1977 Park et al., EnvironToxPharmacol2008 Goodman and Gilman’s The Pharmacological Basis of Therapeutics (10th ed), Eds Hardman and Limbird, McGrowthHall Medical Publishing 2001 Salminen et al., J Pharm Biomed Anal 1997 Pardridge et al., J Neurochem 1985 Padowski & Pollack, J Pharm Sci 2010 Fridén et al., J Med Chem 2009 Assandri et al., J Antiobiot (Tokyo) 1984 Choo et al., Drug Metab Dispos 2000 Evans et al., Drug Metab Dispos 2003 Festuccia et al., Endocrinology 2008 Chapman & McTaggart, Atherosclerosis Suppl 2002 Fridén et al., J Med Chem 2009 http://www.inchem.org/documents/jecfa/jecmono/v34je03.ht m Craig & Kunin, J Infect Dis 1973 Fridén et al., J Med Chem Doran et al., Drug Metab Dispos 2005 Kalvass et al., Drug Metab Dispos 2005 FASS – the Swedish PDR (www.fass.se) http://www.fda.gov/ohrms/dockets/ac/01/briefing/3746b_01_a ventis.html#_Toc37743413 Lockman et al., J Neurochem 2003 5 115 116 Thioguanine Toremifene -1 -1 rat Brain concentration low due to high efflux in BBB Does not penetrate BBB 117 118 119 120 121 Trimethoprim Valdecoxib Vigabatrin Warfarin Zidovudine -1 -1 -1 -1 -1 122 123 124 125 Zolmitriptan Acetaminophen Acetylsalicylic acid Alimemazine -1 1 1 1 monkey mouse rat rat mouse rabbit rat mouse 126 127 128 129 Alprazolam Alprenolol Altretamine Amitriptyline 1 1 1 1 130 131 132 133 Aripiprazole Ascorbic acid Biperiden Bupropion 1 1 1 1 134 135 136 137 138 139 Buspiron Carbamazepine Carisoprodol Celecoxib Chlorcyclizine Chloroquine 1 1 1 1 1 1 140 141 142 143 144 145 Chlorpromazine Chlorzoxazone Citalopram Clemastine Clomethiazole Clompiramine 1 1 1 1 1 1 Brain to plasma ratio <0.3 Brain to plasma ratio 0.05 Brain to plasma ratio of 0.1 Brain to plasma ratio of 0.10 Brain to plasma ratio of 0.10 Brain to plasma ratio of 0.19 Brain to plasma ratio of 0.065 Brain to plasma ratio or 0.04 Brain to blood ratio of 0.49 Brain to blood ratio of 0.32 Brain to plasma ratio of 3.05 (post mortem). N.B. overdose of alimemazine Brain to blood ratio of 1.1 Brain to plasma ratio of 8.27 Brain to plasma ratio of 3.99 Brain to plasma ratio of ~25 Brain to plasma ratio of 20.15 Brain to plasma ratio of ~5 Brain to plasma ratio of ~3 Brain to plasma ratio of 13 Brain to plasma ratio of ~25 Brain to plasma ratio of 9.78 Brain to plasma ratio of 1.6 Brain to plasma ratio of 0.76 Brain to plasma ratio of 0.66 Brain to plasma ratio of 1.7 Brain to plasma ratio of 15 Statement: Brain concentration can be 10-30 fold higher than plasma Brain to blood ratio of 11.5 Brain to plasma ratio of 1 Brain to plasma ratio of 5.1 High penetration into brain Brain to plasma ratio of 1.4 Brain to plasma ratio of 22 human rat mouse mouse rat rat rat rat rat mouse mouse mouse rat rat rat mouse rat gerbil rat Mori et al., J Neurochem 2004 Goodman and Gilman’s The Pharmacological Basis of Therapeutics (10th ed), Eds Hardman and Limbird, McGrowthHall Medical Publishing 2001 Tu et al., J Pharm Sci 1989 Summerfield et al, J Pharmacol Exp Therapeut 2006 Tsong et al., Epilepsia 2003 Urien et al., J Pharmacol Exp Therapeut 1989 Chow et al., Pharm Res 1998 Wang et al., J Pharm Sci 1995 Fridén et al. J Med Chem 2009 Evans et al., Drug Metab Dispos 2003 Salminen et al., J Pharm Biomed Anal 2000 Salminen et al., J Pharm Biomed Anal 2000 Kintz et al, J Anal Toxicol 1995 Salminen et al., J Pharm Biomed Anal 2000 Fridén et al., J Med Chem 2009. Broggini et al., Cancer Treat Rep 1982 Abaut et al., Int J Pharm 2009 Fridén et al., J Med Chem 2009 Shimokawa, J Chromatogr B Analyt Technol Biomed Life Sci 2005 van der Loo et al., Biochim Biophys Res Commun 2003 Ishizaki et al., J Pharm Pharmacol 1998 Schroeder et al., J Clin Psych 1983 Fridén et al., J Med Chem 2009 Doran et al., Drug Metab Dispos 2005 Doran et al., Drug Metab Dispos 2005 Doran et al., Drug Metab Dispos 2005 Okumura et al., Eur J Pharmacol 2006 Kuntzman et al., J Pharmacol Exp Therapeut 1965 Telgt et al., Ann Pharmacother 2005 Salminen et al., J Pharm Biomed Anal 2000 Yasuhara & Levy, Pharm Res 1995 Doran et al., Drug Metab Dispos 2005 Obradovic et al., Pharm Res 2007 Green et al., Br J Pharmacol 2000 Kurata et al., Jpn J Psychiatry Neurol 1986 6 146 147 148 Clonazepam Clonidine Clozapine 1 1 1 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 Codeine Cyclobenzaprine Cyclophosphamide Deferiprone Dexamethasone Dextropropoxyphene Diphenhydramine Donepzil Eletriptan Enrofloxacin Ethosuximide Ethyl-phenylmalonamide Etoricoxib Fentanyl Fluconazole Flunitrazepam Fluoxetine Fluphenazine Fluvoxamine Gabapentin 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 169 170 171 Galantamine Granisetron Haloperidol 1 1 1 172 173 174 175 176 177 Hydrocodone Hydroxychloroquine Hydroxyzine Hyoscyamine Isoniazid Lamotrigine 1 1 1 1 1 1 178 179 Levetiracetam Levomepromazine 1 1 rat mouse rat rat mouse rat mouse rat rat rat mouse canine mouse rat mouse mouse human rat mouse rat mouse rat mouse rat mouse rat mouse rat mouse mouse baboon mouse rat rat human Brain to plasma ratio >0.3 at time≥1h Brain to blood ratio of 1.3 Brain to plasma ratio of 4.1 Brain to plasma ratio of 10.2 Brain to plasma ratio of 2.70 Brain to plasma ratio of 12 Brain to plasma of ~1 Brain to plasma ratio >0.7 Brain to plasma ratio of 0.30 Brain to plasma ratio of 4.4 Brain to plasma ratio of 16.25 Brain to plasma ratio >2 (dose dependent) Brain to plasma ratio of 0.30 Brain to plasma ratio of 0.37 Brain to plasma ratio of 1.1 Brain to plasma ratio of 0.64 Brain to plasma ratio of 0.66 Brain to plasma ratio of 2.4 Brain to blood ratio of 1.3 (PET) Brain to plasma >1 Brain to plasma ratio of 12 Brain to plasma >10 Brain to plasma ratio of 6.1 Brain to blood ratio of 0.75 Brain to plasma ratio of 0.64 Brain to plasma ratio of 2.1 Brain to plasma ratio >0.3 Brain to plasma ratio of 13 Brain to plasma ratio of 18 Brain to plasma ratio of 2.1 Brain to plasma ration of ~2 Brain to plasma ratio of 7.7 Brain to plasma ratio of 0.7 Brain to plasma ~1 (PET) Brain to plasma ratio of 1.1 Brain to plasma ratio of 2.02 Brain to serum ratio of 0.5 Brain to plasma ratio >10 (post mortem) Vyas et al., J Pharm Sci 2006 Salminen et al., J Pharm Biomed Anal 2000 Doran et al., Drug Metab Dispos 2005 Zhang et al., J Chromatogr B 2007 Fridén et al., J Med Chem 2009 Doran et al., Drug Metab Dispos 2005 Product specifications Fredenburg et al., Toxicol 1986 Kalvass et al., Drug Metab Dispos 2005 Due et al., Toxicol Appl Pharmacol 1981 Fridén et al., J Med Chem 2009 Kim et al, J Pharm Sci 2009 Evans et al, Drug Metab Dispos 2003 Product specifications Doran et al., Drug Metab Dispos 2005 Fridén et al., J Med Chem 2009 Summerfield et al, J Pharmacol Exp Therapeut 2006 Kalvass et al., Drug Metab Dispos 2005 Fischman et al., Antimicrob Agents Chemother 1993 Becherucci et al., Pharmacol Res Commun 1985 Doran et al., Drug Metab Dispos 2005 Aravagiri et al., Neuropsychopharmacol 1995 Doran et al., Drug Metab Dispos 2005 Wang & Welty, Pharm Res 1996 Fridén et al., J Med Chem 2009 Bickel et al., Neuropharmacology 1991 Huang et al., Life Sci 1999 Doran et al., Drug Metab Dispos 2005 Zhang et al., J Chromatogr B 2007 Doran et al., Drug Metab Dispos 2005 Wei et al, Chirality 1995 Doran et al., Drug Metab Dispos 2005 Palmer et al., Acta Pharmacol et Toxicol 1981 Liu et al. J Med Chem 2010 Doran et al., Drug Metab Dispos 2005 Fridén et al., J Med Chem 2009 Tong & Patsalos, Br J Pharmacol 2001 Kornhuber, J Neural Transm 2006 7 180 181 182 183 184 185 186 187 Lidocaine Linezolid Loratadine Lorazepam Maprotiline Mefloquine Melperone Memantine 1 1 1 1 1 1 1 1 188 189 190 191 192 Meprobamate Methadon Methylphenidate Metoclopramide Metoprolol 1 1 1 1 1 rat human mouse human rat mouse mouse mouse rat mouse mouse mouse mouse rat 193 Mianserin 1 mouse 194 195 196 197 Midazolam Mirtazepine Modafinil Morphine 1 1 1 1 198 199 200 201 202 203 204 205 206 207 Naltrexone Naratriptan Nevirapine Nitrazepam Norptriptyline Olanzapine Oxazepam Oxprenolol Oxybutynin Oxycodone 1 1 1 1 1 1 1 1 1 1 208 209 210 211 212 Oxymorphone Paroxetine Pentobarbital Perphenazine Pethidine 1 1 1 1 1 human rat mouse rat rat rat mouse guinea pig human mouse rat rat rat rat rat rat mouse human mouse Brain to plasma ratio of 1.6 Brain to serum ratio of 0.45 Brain to plasma ratio of 1.6 Brain to plasma ratio >0.57 AUCbrain/AUCserum of 57 Brain to plasma ratio of 1.31 Brain to plasma ratio of 6.7 Brain to plasma ratio of 30 Brain to plasma ratio >10 Brain to plasma ratio of 0.42 Brain to plasma ratio of 2 Brain to plasma ratio of 12 Brain to plasma ratio of 1.2 Brain to plasma ratio of 0.57 Brain to plasma ratio of 3.14 Cmax,Brain/Cmax, Plasma >10 Brain to blood ratio of 2.3 Brain to plasma ratio of ~10 (PET) Brain to plasma ratio >0.3 Brain to plasma ratio of 0.46 Brain to plasma ratio of 0.56 Brain to plasma ratio of 0.51 Brain to plasma ratio of 0.83 Brain to plasma ratio of 0.42 Brain to plasma ratio >0.3 Brain to plasma ratio >0.3 (post mortem) Brain to plasma ratio of 11 Brain to plasma ratio >5 Brain to plasma ratio >5 Brain to plasma ratio of 1.06 Brain to plasma ratio of 6.27 Brain to plasma ratio of 3 Brain to plasma ratio of 3.77 Brain to plasma ratio of 2.29 Brain to plasma ratio of 3.3 Brain to blood ratio of 1.32 Brain to blood ratio of ~3 (post mortem) Brain to plasma ratio of 6.8 Berry et al., Drug Metab Dispos 2010 Tsona et al., J Chemother 2010 Uchida et al, J Pharmacol Exp Therapeut 2011 Greenblatt et al, Pharm Exp Therapeut 1989 Miyake et al., J Pharm Sci 1992 de Lagerie, Drug Metab Lett 2009 Uhr et al., J Psychopharmacol 2004 Saab & Roder, Pharmacol 2011 Wesemann, Arzneimittelforschung 1989 Doran et al., Drug Metab Dispos 2005 Kalvass et al., Drug Metab Dispos 2007 Doran et al., Drug Metab Dispos 2005 Doran et al., Drug Metab Dispos 2005 Berry et al., Drug Metab Dispos 2010 Fridén et al., J Med Chem 2009 Alta mura et al., Prog Neuropsychopharmacol Biol Psychiatry 1987 Salminen et al., J Pharm Biomed Anal 2000 Smith et al., J Psychopharmacol 2008 Waters et al., J Psychopharmacol 2005 Doran et al., Drug Metab Dispos 2005 Bostrom et al., Anesthesiology 2008 Fridén et al., J Med Chem 2009 Berry et al., Drug Metab Dispos 2010 Kalvass et al., Drug Metab Dispos 2005 Gibbs et al., J Pharmacol Exp Therapeut 2006 Moriya & Hashimoto, Forensic Sci Int Doran et al., Drug Metab Dispos 2005 Aravagiri et al., Biopharm Drug Dispos 1999 Sisenwine & Tio, Drug metab Dispos 1986 Fridén et al., J Med Chem 2009 Callegari et al., Br J Clin Pharmacol 2011 Boström et al., Anesthesiology 2008 Fridén et al., J Med Chem 2009 Fridén et al., J Med Chem 2009 Doran et al., Drug Metab Dispos 2005 Salminen et al., J Pharm Biomed Anal 2000 Levine et al., J Anal Toxicol 1999 Kalvass et al., J Pharmacol Exp Therapeut 2007 8 213 214 215 Phenobarbital Phenylalanine Pindolol 1 1 1 rat mouse, rat rat Brain to plasma ratio of 0.72 Brain to plasma ratio of ~1.2 (mouse) and ~2 (rat) Brain to plasma ratio of 1.56 Brain to plasma ratio of ~4 216 217 Piracetam Prochlorperazine 1 rat Brain to plasma ratio of ~1 Statement: High concentrations reach the brain 218 219 220 221 222 223 224 225 226 227 Promazine Promethazine Propoxyphene Pyrazinamide Pyrilamine Quetiapine Reboxetine Rifabutin Riluzole Risperidone 1 1 1 1 1 1 1 1 1 1 228 229 230 231 232 233 234 235 236 237 Rivastigmine Rofecoxib Selegiline Sertraline Sildenafil Sulfentanil Tacrine Temazolide Theophylline Thiopental 1 1 1 1 1 1 1 1 1 1 238 239 240 Thioridazine Tinidazole Topiramate 1 1 1 241 Tramadol 1 242 243 244 Trazodone Triazolam Trihexyphenidyl 1 1 1 rabbit mouse baboon human mouse, rat rat mouse mouse rat rat rat mouse mouse human mouse rat rat mouse rat rat rat rat mouse rat mouse rat rat Brain to blood ratio of 17 Brain to plasma ratio of 20 Brain to plasma ratio of 2.9 Brain to plasma ratio of ~1.4 (PET) Brain to blood ratio of 3.16 Brain to plasma ratio of ~2 (post mortem) Brain to plasma ratio of >1 Brain to plasma ratio 0.57 Brain to plasma ratio of 2.4 Brain to plasma ratio of 0.78 Brain to plasma ratio of 0.48 AUCbrain/AUCplasma of 3.1 Brain to plasma ratio of 0.47 Brain to plasma ratio of 3.7 Brain to plasma ratio of 24 Brain to blood >100 (post mortem) Brain to plasma ratio of 1.6 Brain to plasma ratio of 9.56 Brain to plasma ratio of 0.35 Brain to blood ratio of 0.52 Brain to plasma ratio of 0.36 Brain to plasma ratio of 1.28 Brain to plasma ratio of 3.75 Brain to plasma ratio of 0.69 Brain to plasma ratio of 0.4 Brain to plasma ratio of 0.84 Brain to plasma ratio >1 (mouse) and >2 (rat) Brain to plasma ratio of 5.29 Brain to plasma ratio of 0.61 AUCbrain/AUCplasma of 0.31 Brain to plasma ratio of 13.7 Leppik & Sherwin, Epilepsia 1979 Murakami et al., Am J Physiol Heart Circ Phys 2000 Fridén et al., J Med Chem 2009 Garvey & Ram, J Pharmacol Exp Therapeut 1975 Yan & Lewander, Eur Neiropsychopharmacol 1999 Tacconi & Wurtman, J Pharm Pharmacol 1984 http://stp.cancercare.ns.ca/documents/Prochlorperazine_dm.p df (accessed Jan 26 2012) Salminen et al., J Pharm Biomed Anal 2000 Yokogawa et al., Pharm Res 1990 Doran et al., Drug Metab Dispos 2005 Liu et al. J Med Chem 2010 Salminen et al., J Pharm Biomed Anal 2000 Hopenwasser et al., J Anal Toxicol 2004 Strolin Benedetti et al., Chirality 1995 Battaglia et al., Antimicrob Agents Chemother 1991 Milane et al., J Pharm Pharmaceut Sci 2009 Doran et al., Drug Metab Dispos 2005 Zhang et al., J Chromatogr B 2007 Arumugam et al., Acta Pharm 2008 Okumura et al., Eur J Pharmacol 2006 Doran et al., Drug Metab Dispos 2005 Doran et al., Drug Metab Dispos 2005 Pagani et al., J Anal Toxicol 2005 Kalvass et al., Drug Metab Dispos 2005 Fridén et al., J Med Chem 2009 Reyderman et al., Xenobiotica 2004 Salminen et al., J Pharm Biomed Anal 2000 Doran et al., Drug Metab Dispos 2005 Fridén et al., J Med Chem 2009 Fridén et al., J Med Chem 2009 Wood et al., J Antimicrob Chemother 1982 http://www.lifescience.co.jp/yk/yk08/jun/ab1.html Fridén et al., J Med Chem 2009 Tao et al., J Clin Pharm Ther 2002 Fridén et al., J Med Chem 2009 Doran et al., Drug Metab Dispos 2005 Nakashima et al., J Pharm Biomed Anal 2003 Ischizaki et al., J Pharm Pharmacol 1998 9 245 246 247 248 249 250 Trimipramine Triprolidine Venlafaxine Vinblastine Ziprasidone Zolpidem 1 1 1 1 1 1 251 Zopiclone 1 mouse mouse mouse mouse rat mouse rat rat Brain to plasma ratio of 7 Brain to plasma ratio of 5.9 Brainto plasma ratio of 4.2 Brain to plasma ratio of 1.7 Brain to plasma ratio of 2.38 Brain to plasma ratio of 0.29 Brain to plasma ratio of 0.32 Brain to plasma ratio >0.3 Ur et al., J Psych Res 2003 Kalvass et al., Drug Metab Dispos 2005 Doran et al., Drug Metab Dispos 2005 Kalvass et al., Drug Metab Dispos 2005 Zhang et al., J Chromatogr B 2007 Doran et al., Drug Metab Dispos 2005 Trenque et al., J Pharm Pharmacol 1994 Fernandez et al., J Pharm Pharmacol 2002 BBMEC = bovine brain microvascular endothelial cells 10 Table SII. Site of radiolabel and specific activities of probe compounds used to generate B:P ratios in Swiss Outbred mice. Compound Alanine Antipyrine Arachidonic acid Arginine Caffeine Carnitine Cholesterol Colchicine Cyclosporine A Decanoic acid Diazepam Digoxin Dopamine Estradiol Glucose Glycine Hypoxanthine Ibuprofen Imipramine Lactic acid Leucine Linoleic acid Linolenic acid Loperamide Mannitol Naproxen Oleic acid Palmitic acid Phenytoin Propranolol Quinidine Saquinavir Sucrose Tamoxifen Urea Valproic acid Verapamil Site of radiolabel U-14C 3-14C 5,6,8,9,11,12,14,15-3H(N) 2,3-3H 1-methyl-14C N-methyl-3H 4-14C Ring C, methoxy-3H mebmt-β-3H 1-3H Methyl-3H 3H(G) 7,8-3H 2,4,6,7-3H(N) 1-14C 2-3H 8-3H Carboxyl 14C Benzene ring-3H(N) 14C(U) U-14C 1-14C 1-14C N-methyl-3H 1-14C O-methyl-14C 1-14C 1-14C 4-14C 4-3H Methyl-3H 1-3H 14C(U) N-methyl-3H 1-14C 4,5-3H N-methyl-3H Specific activity (mCi/mmol) 154 5.4 100,000 42,000 51.2 85,000 50 76,500 7,000 5,000 79,500 21,800 45,000 100,000 262 48,700 19,000 55 47,500 55 306 56 51 85,000 56.5 55 54.6 53 55 18.8 20,000 2,800 600 80,000 55 55,000 70,500 11 Table SIII. Results of CNS exposure predictions of the test set. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Correct High Acetaminophen Acetylsalicylic acid Alimemazine Alprazolam Altretamine Amitriptyline Aripiprazole Ascorbic acid Biperiden Buspiron Carbamazepine Chlorcyclizine Chloroquine Chlorpromazine Chlorzoxazone Citalopram Clemastine Clomethiazole Clomipramine Clonazepam Clonidine Clozapine Cyclobenzapine Cyclophosphamide Deferiprone Dextropropxyphene Diphenhydramine Donepezil Ethosuximide Ethyl-phenylmalonamide Fentanyl 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 Correct High Flunitrazepam Gabapentin Galantamine Granisetron Haloperidol Hydrocodone Hydroxychloroquine Hydroxyzine Isoniazid Lamotrigine Levetiracetam Levomepromazine Lidocaine Loratadine Maprotiline Melperone Memantine Meprobamate Methadon Methylphenidate Mianserin Midazolam Mirtazepine Morphine Nevirapine Nitrazepam Nortiptyline Olanzapine Oxazepam Oxymorphine Paroxetine 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 Correct Low Acamprosate Acarbose Acrivastine Acyclovir Adefovir dipivoxil Alfentanil Almotriptan Ambenonium Amoxicillin Amprenavir Atenolol Atorvastatin Atovaquone Azathioprine Azithromycin Benazepril Benserazide Bicalutamide Biotin Bromocriptine Cabergoline Carbidopa Cefalexin Cefdinir 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 Correct Low Ceftriaxone Cefuroxime Cephaloridine Cetirizine Clindamycin Delavirdine Diclofenac Diflunisal Dihydrostreptomycin Doxorubicin Doxycycline Enalapril Ergotamine Erythromycin Ethambutol Ethinylestradiol Etidronic acid Etoposide Felbamate Fexofenadine Fluvastatin Fosamprenavir Furosemide Fusidic acid 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 Correct High Pentobarbital Perphenazine Pethidine Phenylalanine Piracetam Prochlorperazine Promazine Promethazine Pyrzinamide Pyrilamine Quetiapine Reboxetine Risperidone Selegiline Setraline Sufentanil Tacrine Temozolomide Theophylline Thiopental Thioridazine Trazodon Triazolam Trihexyphenidyl Trimipramine Triprolidine Venlafaxine Ziprasidone Zolpidem Zoplicone 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 Correct Low Ganciclovir Glimepiride Glipizide Glucosamine Halofuginone Hydrochlorothiazide Hydroxycarbamide Indinavir Indomethacin Itraconazole Ivermectin Ketoconazole Ketoprofen Levodopa Levofloxacin Lopinavir Lufenuron M3G M6G Melphalan Mepenzolate Methotrexate Methyldopa Mizolastine 12 165 166 167 168 169 170 171 172 173 Correct Low Moxalactam Moxidectin Nadolol Nitrofurantoin Norfloxacin Oxytetracycline Paclitaxel PenicillinV Pivmecillinam 174 175 176 177 178 179 180 181 182 Correct Low Raloxifene Ranitidine Rifampicin Rifapentine Ritonavir Rosiglitazone Rosuvastatin Streptomycin Sulfamethoxazole 183 184 185 186 187 188 189 190 Correct Low Sulphasalazine Sulpiride Sumatriptan Teicoplanin Telithromycin Trimethoprim Valdecoxib Zidovudine 191 192 193 194 195 196 197 198 False High Baclofen Captopril Cimetidine Desloratadine Dipyridamole Ergocalciferol Fluorouracil Mercaptopurine 199 200 201 202 203 204 205 206 False High Mesalazine Metronidazole Nelfinavir Nicotinic acid Orlistat Phytomenadione Pyridostigmine Retinol 207 208 209 210 211 212 213 214 False High Rizatriptan Salicylic acid Thiamine Thioguanine Toremifene Warfarin Vigabatrin Zolmitriptan 215 216 217 218 219 220 221 222 223 224 225 226 227 False Low Alprenolol Bupropion Carisoprodol Celecoxib Codeine Dexamethasone Eletriptan Enrofloxacin Etoricoxib Fluconazole Fluoxetine Fluphenazine Fluvoxamine 228 229 230 231 232 233 234 235 236 237 238 239 False Low Hyoscyamine Linezolide Lorazepam Mefloquine Metoclopramide Metoprolol Modafinil Naltrexone Naratriptan Oxprenolol Oxybutynine Oxycodone 240 241 242 243 244 245 246 247 248 249 250 251 False Low Phenobarbital Pindolol Propoxyphene Rifabutin Riluzole Rivastigmine Rofecoxib Sildenafil Tinidazol Topiramate Tramadol Vinblastine 13
