SUPPLEMENTARY MATERIALS

Title:

A Review of Food-Drug Interactions on Oral Drug Absorption

Mechanisms and Clinical Significance of Food Effect

Authors:

Jianyuan Deng (1) ∙ Xiao Zhu (1) ∙ Zongmeng Chen (2) ∙ Chun Ho Fan (1) ∙ Him Shek Kwan (1) ∙ Chi Ho Wong

(1) ∙ Ka Yi Shek (1) ∙ Zhong Zuo (1) ∙ Tai Ning Lam (1)

Affiliations:

(1) School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories

Hong Kong, HONG KONG

(2) State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical

University, Nanjing, Jiangsu Province, People's Republic of China

Corresponding author contact:

Email: teddylam@cuhk.edu.hk (TNL)

Phone number: (852) 3943 6827

Fax number: (852) 2603 5295

1

Supplementary Table S1 Experiment Schemes of Collected Food Effect Studies

Drugs Dose (mg) No. Character of Subjects Formulation Food Volume (mL) Drug-Food Interval Sample References

Abacavir sulfate $ 300 18 HIV infected patients Tablet High-fat 150 NA Plasma [1]

Acetylsalicylic acid $ 350 8 Healthy volunteers Doleron ® Tablet Standard 100 0 Plasma [2]

Aliskiren $ 300 30 Healthy subjects Tablet High-fat NA 0.5 hoursh Plasma [3]

Alprazolam $ 1 16 Healthy volunteers Tablet High-fat 240 0.5 h Plasma [4]

Antipyrine $ 65 8 Healthy volunteers Doleron ® Tablet Standard 100 0 Plasma [2]

Bromazepam $ 10 7 Normal volunteers Lexotan® Tablet Standard 200 0.5 hoursh Plasma [5]

Bromocriptine $ 5 7 Healthy male subjects Capsule Standard NA 10 minutesmin Plasma [6]

Budesonide $ 9 12 Healthy Caucasians MMX® Tablet High-fat NA 0.5 hoursh Plasma [7]

Capecitabine $ NA 5 Colorectal cancer patients Tablet Standard NA 0.5 hoursh Plasma [8]

Chlorambucil 40 5 Elderly leukemia patients Leukeran Tablet Standard 100 NA Plasma [9]

Cilazapril $ 5 16 Healthy volunteers Capsule Standard 240 NA Plasma, urine [10]

Clobazam $ 10 6 Healthy volunteers Tablet Standard 250 3 hoursh Plasma [11]

Cyclobenzaprine $ 30 15 Healthy volunteers Amrix® Capsule High-fat 180 0 Plasma [12]

Diazepam $ 5 6 Healthy volunteers Valium® Tablet Typical 30 0 Plasma [13]

Diclofenac $ 50 8 Healthy volunteers Gelatin Capsule Standard 150 NA Serum [14]

Dilevalol $ 400 12 Healthy male volunteers Tablet High-fat NA NA Plasma, urine [15]

Diltiazem $ 60, 120 24 Male volunteers IR Tablet, SR Capsule Standard 200 0.5 hoursh Plasma [16]

Doxazosin $ 1 12 Elderly with hypertension Tablet Standard 200 0 Plasma [17]

Enalapril $ 40 12 Normal volunteers Tablet Standard NA 0 Serum [18]

Escitalopram $ 20 18 Healthy volunteers Tablet High-fat NA 0.5 hoursh Plasma [19]

Esomeprazole magnesium $ 40 44 Healthy volunteers Capsule High-fat NA -0.25 hoursh Plasma [20]

Ethinylestradiol $ 0.02 18 Postmenopausal Tablet High-fat 240 0.25 Plasma [21]

Everolimus $ 2 24 Healthy subjects Tablet High-fat 200 0.25 hoursh Blood [22]

2

Fluvastatin sodium 10 24 Healthy men Capsule, solution High-fat NA 0 Blood [23]

Fluvoxamine $ 50 12 Healthy volunteers Tablet Standard 480 0.25 hoursh Plasma [24]

Hydrocodone 20 12 Healthy volunteers Capsule High-fat NA 0.5 hoursh Plasma [25]

Hydrocortisone 60 NA Healthy volunteers NA Standard NA 0 Plasma [26]

Hydromorphone $ 16 27 Healthy volunteers OROS® High-fat NA 0 Plasma [27]

Hydroxychloroquine sulfate $ 155 9 Healthy subjects PlaquenilTM tablet High-fat 200 0.5 hoursh Blood [28]

Idarubicin 35 (/m2) 10 Patients with solid tumors NA Standard NA NA Plasma [29]

Imipramine $ 50 12 Healthy volunteers NA Standard 100 0.5 hoursh Plasma [30]

Isoniazid $ 300 14 Healthy subjects NA High-fat NA 0.25 hoursh Serum [31]

Isosorbide mononitrate $ 60 18 Healthy men IMDUR® Tablet High-fat 184 5 minutesmin Plasma [32]

Labetalol $ 200 6 Healthy volunteers NA Standard NA 0 Plasma [33]

Letrozole $ 2.5 12 Healthy male Tablet High-fat 200 0.25 hoursh Plasma [34]

Melphalan 4.2~5.3 (/m2) 10 Patients NA Standard NA NA Plasma [35]

Metoprolol $ 190 12 Non-smoking males OROS Normal NA NA Plasma [36]

Metronidazole $ 125 23 Caucasians Capsule High-fat 240 0.5 hoursh Blood [37]

Midazolam hydrochloride $ 15 18 Healthy volunteers Tablet Standard NA 1 hourh Plasma [38]

Minocycline hydrochloride $ 100 16 Healthy volunteers NA NA 174 NA Serum [39]

Mirtazapine $ 15 19 Normal young male Tablet High-fat 240 0 Plasma [40]

Misoprostol $ 0.4 12 Healthy male Tablet High-fat 180 0 Plasma [41]

Morphine hydrochloride $ 50 5 Patients Solution High-fat 50 0 Blood [42]

Nicardipine 30 17 Adult male Zenith Tablet Standard 240 0.5 hoursh Plasma [43]

Norethindrone $ 2 18 Postmenopausal female Tablet High-fat 120 0 Plasma [21]

Norgestimate $ 0.18 24 Postmenopausal female Tablet High-fat 240 10 minutesmin Serum [44]

Nortriptyline $ 25 9 Female Tablet Standard 150 0 Plasma [45]

Omeprazole $ 20 57 Normal subjects Enteric coated tablet Standard NA 0 Plasma [46]

3

Ondansetron $ 8 12 Healthy male Tablet Standard NA 5 minutesmin Plasma [47]

Oxprenolol $ 80, 160 9 Healthy females Conventional, SR tablet Standard 100 0 Plasma [48]

Oxybutynin hydrochloride $ 10 23 Healthy volunteers Crystrin® Tablet High-fat 200 NA Serum [49]

Oxycodone $ 20 22 Normal subjects Oral solution High-fat 200 5 minutesmin Plasma [50]

Pantoprazole sodium $ 40 19 Healthy subjects Enteric-coated Tablet Standard NA 0 NA [51]

Paracetamol $ 650 24 Young and elderly Tablet, Elixir Standard 100-200, 19.5 0.5 hoursh Plasma [52]

Paroxetine $ 30 41 Healthy males NA Continental NA 0 Plasma [53]

Pefloxacin $ 400 12 Healthy volunteers NA Standard / High-fat NA NA Plasma [54]

Pentoxifylline $ 400 16 Healthy males Capsules Standard NA 0.25 hoursh Plasma [55]

Perindopril erbumine $ 4 12 Healthy subjects NA Standard NA 0 Serum [56]

Primaquine $ 30 20 Healthy Vietnamese Tablet Medium-fat 300 5 minutesmin Plasma [57]

Propantheline bromide 30 10 Normal subjects Tablets NA NA NA Serum [58]

Propranolol hydrochloride $ 80 11 Healthy women Inderal Tablet Standard 100 NA Serum [59]

Propylthiouracil $ 300 8 Healthy volunteers Tablets Standard 100 0 Serum [60]

Pyrazinamide $ 1500, 2000 27 Tuberculosis patients Tablets High-fat 200 NA Plasma [61]

Rabeprazole sodium $ 20 12 Healthy males NA Standard NA -0.5 hoursh NA [62]

Ramipril $ 10 10 Heathy males NA Standard NA NA Serum [63]

Reboxetine 4 12 Healthy young males Tablet High-fat NA NA Plasma [64]

Ribavirin 600 20 Healthy participants Film-coated tablets High-purine 240 0.5 hoursh Plasma [65]

Riluzole $ 100 16 Healthy males Tablet High-fat NA NA Plasma [66]

Rimantadine hydrochloride $ 100 12 Healthy subjects Tablet Standard 240 0 Plasma [67]

Rizatriptan $ 40 12 Healthy males NA Standard NA 5 minutesmin Plasma [68]

Ropinirole $ 2 12 Parkinson patients NA High-fat NA NA Plasma [69]

Selegiline $ 5 11 Healthy volunteers Eldepryl® Tablet High-fat 240 0 Plasma [70]

Sertraline hydrochloride 100 24 Healthy male volunteers Tablet Standard NA 0.5 hoursh Plasma [71]

4

Sibutramine 20 20 Healthy subjects NA Breakfast NA NA Plasma [72]

Sildenafil $ 100 34 Healthy males Tablet High-fat 240 5 minutesmin Plasma [73]

Solifenacin succinate $ 10 12 Healthy males Vesicare® Tablet High-fat 180 5 minutesmin Plasma [74]

Sunitinib malate $ 50 16 Healthy subjects Capsule High-fat NA 0.5 hoursh Plasma [75]

Tacrine $ 40 24 Healthy volunteers Cognex® Capsule Standard NA -1/0.25/2 hoursh Plasma [76]

Tenoxicam $ 20 12 Healthy volunteers NA Standard 200 NA Plasma [77]

Terazosin $ 2 12 NA NA Standard 100 NA Plasma [78]

Theophylline 270 8 Healthy adults Aqueous solution NA 150 NA Plasma [79]

Ticlopidine $ 250 12 Normal volunteers Tablet High-fat 200 0.5 hoursh Plasma [80]

Timolol $ 10 12 Healthy volunteers NA Standard NA NA Serum [81]

Tolterodine $ 2 22 Healthy volunteers NA Standard 150 0 Serum [82]

Urapidil 30 12 Healthy volunteers Tablet, capsule Standard NA NA NA [83]

Valproic acid $ 300 16 Healthy volunteers SR formulation High-fat NA NA Serum [84]

Vardenafil $ 20 25 Healthy adults Levitra® High-fat NA 5 minutesmin Plasma [85]

Venlafaxine hydrochloride $ 50 19 Healthy adults Tablet Standard NA 0.5 hoursh Plasma [86]

Verapamil hydrochloride 80 12 Healthy volunteers Conventional Tablet High-protein NA 0.5 hoursh Plasma [87]

Vinorelbine tartrate $ 80 (/m2) 18 Patients Soft-gel capsule Standard NA 0.25 hoursh Plasma and blood [88]

Zidovudine 100, 250 8 Patients NA High-fat NA 0 Serum [89]

Zolmitriptan $ 5 16 Healthy volunteers NA Standard NA NA Plasma [90]

Zolpidem tartrate 10 30 Healthy male volunteers NA NA NA 20 minutesmin NA [91]

Acitretin $ 50 18 Healthy male volunteers Capsules Standard 240 0 Plasma [92]

Albendazole $ 400 6 Patients NA Fatty 200 0 Plasma [93]

Amiodarone hydrochloride $ 600 30 Healthy subjects Tablets High-fat NA 0 Plasma [94]

Aprepitant $ 80, 125 21 Healthy volunteers EMEND® capsule Standard 226.8 0.25 hoursh Plasma [95]

Armodafinil 100 6 Healthy subjects NA Fatty NA 0 Plasma [96]

5

Artemether $ 80 16 Healthy male volunteers NA High-fat NA 15-25 minutesmin Plasma [97]

Atazanavir sulfate 400 32 Healthy volunteers NA Fatty / Light NA 0 NA [98]

Atorvastatin calcium $ 80 16 Healthy volunteers Capsule Medium-fat 226.8 0 Plasma [99]

Bevantolol $ 100 12 Healthy volunteers Film-coated tablet Standard 200 0.25/-0.25 hoursh Plasma [100]

Bicalutamide $ 50 15 Healthy volunteers Film-coated tablet High-fat NA NA Plasma [101]

Bosentan $ 125 16 Healthy male volunteers Tablets Fat-rich 150 0.5 hoursh Plasma [102]

Buspirone $ 20 8 NA NA Full NA 0.25 hoursh Plasma [103]

Cabergoline $ 1 12 Healthy volunteers Tablets Standard 200 0 Plasma [104]

Carbamazepine $ 6 (/kg) 6 Normal drug-free volunteers Tablets Hospital 100 0 Serum [105]

Carvedilol $ 50 8 Elderly NA Standard NA 0 Plasma [106]

Cefpodoxime proxetil $ 200 16 Healthy subjects Film-coated tablets Normal, High- / Low- protein / fat 240 0 Plasma [107]

Cilostazol $ 100 15 Healthy adult male Tablets High-fat 180 10 minutesmin Plasma [108]

Cinacalcet $ 90 29 Patients with kidney disease Sensipar®/Mimpara® High -/Low- fat NA 0 Plasma [109]

Clofazimine $ 200 3 Healthy volunteers NA NA NA 0 Plasma [110]

Clozapine $ 75 7 Patients Tablets Standard 120 0 Plasma [111]

Cyclosporine $ 6 (/kg) 11 Healthy volunteers Capsule Light breakfast 150 0 Blood [112]

Danazol $ 100 8 Healthy male Capsule Lipid-rich 200 0 Plasma [113]

Darunavir $ 400 23 Healthy volunteers Tablet Standard NA 0 Plasma [114]

Desloratadine $ 7.5 18 Healthy volunteers Film-coated tablet High-fat 180 0 Plasma [115]

Dicoumarol 250 10 Healthy volunteers Non-micronized form Standard NA 0 Serum [116]

Ebastine $ 10, 20 18 Healthy male volunteers Tablets High- / Low- fat 226.8 0 Plasma [117]

Erlotinib hydrochloride $ 100 11 Healthy individuals Film-coated tablet High-fat 200 0 Plasma [118]

Etravirine $ 100 12 Healthy volunteers Tablet Standard 200 10 minutesmin Plasma [119]

Febuxostat $ 40, 120 24 Healthy subjects NA High-fat NA 0.5 hoursh Plasma [120]

Fenofibrate $ 145 45 NA Nanoparticle tablet High- / Low- fat NA NA NA [121]

6

Flurbiprofen $ 200 20 Healthy Indian males Froben® SR Capsules Heavy 120 0 Plasma [122]

Gefitinib $ 250 25 Healthy volunteers IRESSA® tablet High fat NA 0.5 hoursh Plasma [123]

Glipizide $ 5 9 Healthy subjects Tablets Standard NA 0 Blood [124]

Griseofulvin $ 125 4 Healthy males (Ultra-)microsize Standard 200 0.25 hoursh Serum [125]

Ibuprofen $ 600 20 Healthy volunteers Brufen Retard® Heavy 200 0.5 hoursh Serum [122]

Iloperidone 3 22 Healthy volunteers NA NA NA 0.25 hoursh Plasma [126]

Indinavir sulfate $ 600 7 HIV+ male volunteers CrixivanTM capsules Fat, protein, carbohydrate, viscous 100 0 Plasma [127]

Indobufen $ 100 6 Healthy volunteers Tablet Normal NA NA Plasma, urine [128]

Indomethacin $ 25 5 Healthy volunteers Capsules Normal 200 0.25 hoursh Serum [129]

Irbesartan $ 300 16 Healthy male volunteers Tablet High-fat NA 5 minutesmin Plasma [130]

Isradipine $ 10 15 Normal subjects Capsule Standard NA 0 Plasma [131]

Itraconazole $ 100 12 Healthy subjects Diflucan® Capsules Light, Full 100 5 minutesmin Plasma [132]

Ketoconazole $ 200~800 8 Healthy adults Nizoral® Standard 100 0 Serum [133]

Ketoprofen $ 100 12 Patients Capsules Standard 100 0 Plasma [134]

Lamotrigine $ 100 9 Healthy male volunteers Lamitor® tablets High-fat 240 0.5 hoursh Plasma [135]

Lansoprazole $ 30 12 Healthy subjects Enteric-coated granules Standard NA 0 Plasma [136]

Lapatinib ditosylate $ 1500 27 Patients with solid tumor Tablets Low- / High- fat 0 0 Plasma [137]

Loratadine $ 10 24 Healthy volunteers Tablet High-fat 180 5 minutesmin Plasma [138]

Losartan potassium $ 100 59 Healthy subjects COZAAR® Tablet High-fat NA 0.5 hoursh Plasma [139]

Mefenamic acid $ 250 4 Healthy male volunteers Capsules Standard 50 0 Plasma [140]

Mefloquine $ 750 20 Healthy male volunteers Lariam Tablet High-fat 200,100 10 minutesmin Plasma, urine [141]

Meloxicam $ 15 16 Healthy male Caucasians Capsule High-fat NA 0 Plasma [142]

Mercaptopurine 31.2~81.1 (/m2) 7 Patients NA Standard NA -0.25 hoursh Plasma [143]

Mycophenolate mofetil $ 2000 10 Rheumatoid arthritis Capsules High-fat 180 0.5 hoursh Plasma [144]

Nabumetone 1000 12 Healthy subjects Tablets NA NA 0 Plasma [145]

7

Nateglinide $ 60 12 Healthy subjects Film-coated tablets High-fat NA 0 Plasma [146]

Nefazodone $ 200 24 Healthy adult male volunteers Tablets High-fat 240 5 minutesmin Plasma [147]

Nelfinavir $ 1250 52 Healthy male subjects Tablets Standard NA 0 Plasma [148]

Nifedipine $ 10 15 Healthy subjects Capsule High-fat 120 0 Plasma [149]

Nilotinib $ 400 44 Healthy subjects NA High- / low- fat NA 0.5/2 hoursh Serum [150]

Nilvadipine $ 6 8 Healthy volunteers Tablet 464, 748 kcal 200 0.5 hoursh Plasma [151]

Nimesulide $ 100 18 Healthy males Tablets American NA NA NA [152]

Nitrazepam $ 5 7 Healthy male volunteers Benzalin tablets Light 200 0.5 hoursh Plasma [153]

Nitrendipine 0.57, 0.59 (/kg) 5 Young with hypertension Tablet NA NA NA Plasma [154]

Norethindrone acetate $ 2 18 Postmenopausal female Tablets High-fat 226.8 0 Plasma [21]

Oxaprozin $ 1200 12 Healthy volunteers Tablets Standard NA 0 Plasma [155]

Oxcarbazepine $ 600 6 Healthy volunteers Trileptal® Tablet Standard 100 0 Plasma [156]

Phenytoin sodium $ 300 8 Healthy subjects NA Standard 50 0 Serum [157]

Pioglitazone $ 15 28 Healthy subjects Tablets High-fat NA NA Serum [158]

Posaconazole $ 200 (/5 mL) 20 Healthy men Suspension High-/Non- fat NA 5 minutesmin Plasma [159]

Praziquantel $ 1800 9 Healthy volunteers Tablets High- lipid / carbohydrate NA NA Plasma [160]

Prednisone $ 10 4 Healthy male volunteers Danbury/Schering tablet Heavy 170 0 Plasma [161]

Propafenone hydrochloride $ 300 24 Healthy volunteers NA Standard 200 0 Plasma [162]

Propoxyphene napsylate $ 65 8 Healthy volunteers Doleron® Tablet Standard 100 0 Plasma [2]

Quazepam $ 20 21 Healthy male volunteers Tablet Light 200 0.5 hoursh Plasma [153]

Quinapril $ 40 12 Healthy volunteers NA Standard 200 10 minutesmin Plasma [163]

Raltegravir potassium $ 400 19 Healthy subjects NA Low-/medium-/high- fat NA NA Plasma [164]

Rifabutin $ 150 12 Healthy male volunteers Capsule High-fat NA 0.25 hoursh Plasma [165]

Rifampin $ 600 14 Healthy volunteers NA High-fat NA 0.25 hoursh Serum [166]

Rufinamide $ 600 12 Healthy volunteers Film-coated tablets Fat & protein-rich 100 0 Plasma [167]

8

Saquinavir methanesulfonate 600 8 Healthy volunteers Hard gelatin capsules Heavy 150 5 minutesmin Plasma [168]

Sirolimus $ 15 22 Healthy volunteers Solution High-fat 240 10 minutesmin Plasma [169]

Spironolactone $ 200 9 Healthy volunteers Tablets Standard 50 0 Serum [170]

Tacrolimus $ 5 15 Healthy males Capsules High-/low- fat 180 5 minutesmin Blood [171]

Tegaserod maleate $ 12 18 Healthy subjects NA Fat-rich NA -0.5~2.5 h hoursh Plasma [172]

Telithromycin $ 800 18 Healthy male subjects Film-coated tablets High-fat 240 0 High fat [173]

Terbinafine 250 30 Healthy young and elderly Lamisil® NA NA NA Plasma [174]

Terfenadine $ 120 24 Healthy adult male volunteers Seldane® tablets High-fat 200 0 Plasma [175]

Thalidomide $ 200 13 Healthy men and women Celgene capsules High-fat 240 NA Plasma [176]

Tibolone 2.5 24 Postmenopausal women Tablets High-fat NA 0.5 hoursh Plasma [177]

Tipranavir $ 900 12 NA Capsules High-fat NA 0 NA [178]

Tizanidine $ 8 81 Healthy volunteers Capsules High-fat 240 5 minutesmin Plasma [179]

Tolbutamide $ 500 9 Young healthy volunteers Artosin® tablets Standard NA 0 Serum [180]

Tolvaptan 15 19 Japanese NA Japanese NA NA Plasma [181]

Triclabendazole $ 10/kg 20 Patients with fascioliasis NA High-energy NA 0 Plasma [182]

Voriconazole $ 200 12 Healthy volunteers Capsule High-fat NA NA Plasma [183]

Zileuton $ 600 18 Healthy male volunteers Tablet High-fat 180 0.5 hoursh Plasma [184]

Ziprasidone hydrochloride $ 20 8 Healthy male volunteers Capsules High-fat 240 0 Serum [185]

Adefovir dipivoxil 500 10 HIV+ patients Tablet NA NA NA Serum [186]

Albuterol $ 4 24 Healthy male volunteers Volmax® Tablets Standard 250 0 Plasma [187]

Almotriptan 25 16 Healthy volunteers NA NA 150 0 Plasma [188]

Amoxicillin $ 500 16 Normal subjects Capsules Standard 120 0.25 hoursh Serum [189]

Ampicillin $ 500 16 Normal subjects Capsules Standard 120 0.25 h Serum [189]

Atenolol $ 100 10 Healthy volunteers Tenormin® tablet Standard 100 0 Serum [190]

Azithromycin 500,1000,500 52 NA Tablets, sachet, suspension High-fat 240 0 Serum [191]

9

Bendroflumethiazide $ 10 8 Healthy subjects Salures tablets Standard NA NA Plasma [192]

Bisoprolol fumarate 10 6 Healthy male subjects Tablets Standard NA NA Plasma [193]

Bumetanide $ 2 8 Healthy male subjects Burinex® Solution Standard 100 0 Plasma [194]

Captopril $ 100 12 Healthy subjects Tablets Standard 250 0 Blood [195]

Cefaclor $ 250 12 Healthy male volunteers Capsule Standard 150 0.5 hoursh Plasma [196]

Cephradine 500 14 Normal male volunteers Capsules 890 kcal NA 0 Serum [197]

Chloroquine $ 600 7 Healthy adult male volunteers NA Standard NA 0 Plasma [198]

Cimetidine $ 400 18 Healthy male volunteers Tablet Standard 100 NA Plasma [199]

Clavulanic acid $ 750 18 Healthy subjects Tablets Standard 50 0 Serum [200]

Cycloserine $ 500 12 Healthy volunteers NA High-fat NA 0 Plasma [201]

Desmopressin $ 0.4 16 Healthy subjects Minirin® Tablets Standard NA 0/0.5 hoursh Plasma [202]

Desvenlafaxine $ 200 33 Healthy subjects Tablet Low- / medium- / high- fat NA 0.1 hoursh Plasma [203]

Didanosine $ 375 8 HIV+ male subjects Chewable Tablet Standard 120 0.1 hoursh Plasma [204]

Digoxin $ 1.0 6 Healthy volunteers Lanoxin® Tablets Standard NA 0/1.5 hoursh Plasma [205]

Doxycycline $ 200 6 Healthy volunteers Capsules High- carbohydrate / fat / protein 250 0 Serum [206]

Emtricitabine $ NA 24 Healthy subjects NA Light/high-fat NA NA Plasma [207]

Entecavir $ 1 12 Healthy volunteers Dispersible tablets Standard 250 0 Plasma [208]

Ethambutol $ 25 (/kg) 16 Healthy subjects Tablets High-fat 240 0.25 hoursh Serum, [209]

Etoposide $ 100 11 Small cell lung carcinoma Capsule Standard 50 0 Plasma [210]

Famotidine $ 40 17 Healthy volunteers Tablet Standard 150 0 Plasma [211]

Fexofenadine $ 80, 120 NA Healthy males Capsules, tablets High-fat NA 0.5 hoursh Plasma [212]

Fluconazole $ 100 24 Healthy subjects Diflucan® Capsules Light, Full 100 0.1 hoursh Plasma [132]

Fosfomycin tromethamine $ 1876 6 Healthy volunteers Sachet Standard 200 0 Serum [213]

Gabapentin 600 10 Healthy volunteers NA High-protein 240 0.1 hoursh Serum [214]

Ganciclovir sodium $ 1000 20 HIV+, CMV+ patients Hard gelatin capsules Standard 200 0 Serum [215]

10

Hydrochlorothiazide $ 75 8 Healthy volunteers Esidrex® tablets Standard NA 0 Plasma, urine [216]

Lamivudine $ 50 12 HIV+ patients Capsules High-fat NA 0 NA [217]

Leucovorin $ 30 25 Cancer patients Tablets High-fat 148 0.1 hoursh Plasma [218]

Levetiracetam $ 500 10 Healthy adult volunteers Tablet Semisolid 120 NA Serum [219]

Levofloxacin $ 500 24 Healthy subjects Tablet High-fat 237 0 Plasma [220]

Lisinopril $ 20 18 Normal volunteers Tablet Standard 350 0 Serum [221]

Lomefloxacin $ 400 12 Healthy subjects Capsules Standard, high-fat 200 5 minutesmin Plasma [222]

Metformin $ 850 24 Healthy subjects Tablets High-fat 240 5~10 minutesmin Plasma [223]

Methotrexate $ 7.5 12 Healthy male volunteers Tablets High-fat 240 10 minutesmin Serum [224]

Metoclopramide $ 30 16 Healthy male volunteers Sustained-release form High-fat NA NA Plasma [225]

Miglustat $ 100 24 Healthy subjects Capsule Standard 200 0.5 hoursh Plasma [226]

Moxifloxacin hydrochloride $ 400 18 Healthy volunteers NA High-fat NA 0 Serum [227]

Nadolol 80 12 Healthy male subjects Tablets Standard NA 0.5 hoursh Plasma [228]

Nizatidine 150 10 Healthy volunteers Capsule NA NA 2 hoursh Plasma, Serum [229]

Ofloxacin $ 200 12 Healthy male volunteers NA Fat-rich 0 NA Plasma [230]

Penicillamine $ 500 6 Healthy men Tablets Standard 200 0 Plasma [231]

Pirenzepine $ 50 20 Healthy male volunteers Tablet Standard 237 -1.5/0 hoursh Plasma [232]

Pramipexole $ 0.375 15 Healthy male volunteers ER form High-fat NA 0.5 hoursh Plasma [233]

Procainamide $ NA 8 Male Patients NA Hospital NA 0 Serum [234]

Pseudoephedrine $ 240 24 Healthy volunteers ER tablets High-fat 180 5 minutesmin Plasma [138]

Pyridostigmine 120 5 Healthy male subjects Mestinon® Low-fat 100 0 Plasma [235]

Ranitidine $ 100 6 Healthy volunteers Tablets Standard 150 NA Plasma [236]

Risedronate 5 11 Healthy male adult volunteers Capsules High-calcium 150 -0.5/0.5/3 hoursh Plasma [237]

Saxagliptin $ 10 14 Healthy subjects Tablet High-fat 240 0.5 hoursh Plasma [238]

Sitagliptin 100 22 Healthy volunteers Tablet High-fat 240 5 minutesmin Plasma [239]

11

Sotalol $ 160 5 Healthy volunteers Sotacor® tablet Standard 50 NA Serum [240]

Stavudine $ 70 15 HIV+ subjects NA High-fat NA 5 minutesmin Plasma [241]

Sulpiride $ 100 3 Healthy male volunteers Film-coated tablet Standard 100 NA Urine [242]

Talinolol $ 100 8 Healthy male volunteers Fast-disintegrating capsules Standard 200 -1 hoursh Serum [243]

Tenofovir disoproxil $ 600 13 HIV+ Adults Tablet High-fat NA NA Serum [244]

Tetracycline hydrochloride $ 250 8 Healthy volunteers NA Breakfast 177 NA Serum [39]

Topiramate $ 100, 400 18 Healthy male volunteers Tablet High-fat 200 0.25 hoursh Plasma [245]

Topotecan $ 2.3 (/m2) 18 Patients with solid tumors Gelatin capsules High-fat 200 0.25 hoursh Plasma [246]

Vigabatrin $ 1000 8 Healthy male volunteers Tablets Standard French NA 1 hourh Plasma [247]

Zalcitabine $ 1.5 20 HIV+ patients Film-coated tablets Standard 240 0 Plasma [248]

Acyclovir $ 400 (/20 mL) 6 Healthy volunteers Suspension Heavy / light 100 0 Plasma [249]

Atovaquone 500 18, 12 Healthy male volunteers Tablets High-fat / Toast NA 0.75 hoursh Plasma [250]

Cefixime $ 400 20 Healthy adult volunteers Capsules Standard 250 0.25 hoursh Serum [251]

Cefprozil $ 250 12 Healthy male volunteers Capsules Standard 150 0.5 hoursh Plasma [196]

Chlorothiazide 500 9 Healthy male volunteers Tablets Standard 250 0 Plasma [252]

Cinoxacin $ 500 10 Healthy male volunteers Capsules Standard NA NA Serum, urine [253]

Ciprofloxacin $ 750 12 Healthy male volunteers NA Standard NA 0/2 hoursh Plasma [254]

Enoxacin $ 400 15 Healthy subjects Capsules High-fat 100 5 minutesmin Plasma [255]

Eprosartan $ 300 17 Healthy males Tablets High-fat 240 NA Plasma [256]

Erythromycin stearate $ 500 6 Healthy subjects Film-coated tablets High-fat 250 0 Serum [257]

Fleroxacin $ 400 20 Healthy subjects NA Standard 120 0 Serum [258]

Furosemide $ 40 8 Healthy subjects Lasix Tablet Breakfast 200 NA Plasma [259]

Lenalidomide $ 25 16 Healthy subjects NA High-fat NA 0 Plasma [260]

Norfloxacin 200 6 Healthy male volunteers Baccidal® tablets Milk 200 (milk) 0 Serum [261]

Roxithromycin $ NA NA NA NA Standard NA 0.25 hoursh NA [262]

12

No: number of subjects participating in clinical food effect study. Food: standard means Standard/Normal diet/breakfast/meal; high-fat means fatty/fat-rich/heavy/high-fat/energy/lipid(-rich) diet/breakfast/meal; low-

fat means (standard/standardized) light/non-fat/low-fat/lipid/energy diet/breakfast/meal; high-carbohydrate for high-carbohydrate diet/breakfast/meal; high-protein for high-protein diet/breakfast/meal; low-protein for

low-protein diet/breakfast/meal; high-calcium for high-calcium diet/breakfast/meal. Vol: volume of water taken with drugs. Interval: the time interval of drug administration after food intake; a hyphen or minus

symbol represents drug is taken before a meal. Sample: type of biological samples taken. NA: not available. $: Mark for cases used for BDDCS in food effect prediction.

13

Supplementary Table S2 Results of Collected Food Effect Studies in Supplementary Table S1

Drugs BDDCS

Class

Absorption Rate Measures & Statistical Significance Absorption Extent Measures & Statistical Significance References Level

Tmax Tested Cmax Tested AUC Tested F Tested

Abacavir sulfate $ I ↑ √ ↓ √ ↔ √ [1] I

Acetylsalicylic acid $ I ↔ √ ↔ √ ↔ √ [2] II-1

Aliskiren $ I ↑ √ ↓ √ ↓ √ [3] I

Alprazolam $ I ↑ ↓ √ ↔ √ [4] I

Antipyrine $ I ↔ √ ↔ √ ↔ √ [2] II-1

Bromazepam $ I ↔ √ ↓ √ ↓ √ [5] II-1

Bromocriptine $ I ↔ √ ↓ √ ↔ √ [6] II-1

Budesonide $ I ↔ √ ↓ √ ↓ √ [7] I

Capecitabine $ I ↑ √ ↓ √ ↓ √ [8] I

Chlorambucil I ↑ ↓ ↔ [9] II-1

Cilazapril $ I ↑ √ ↓ √ ↓ √ [10] I

Clobazam $ I ↔ √ ↓ √ ↔ √ [11] I

Cyclobenzaprine $ I ↔ √ ↑ √ ↑ √ [12] I

Diazepam $ I ↑ √ ↓ √ ↑ √ [13] II-3

Diclofenac $ I ↑ √ ↓ √ ↔ √ [14] II-1

Dilevalol $ I ↔ √ ↔ √ ↔ √ [15] 1

Diltiazem $ I ↔ √ ↔ √ ↔ √ [16] I

Doxazosin $ I ↔ √ ↔ √ ↔ √ [17] I

Enalapril $ I ↔ √ ↔ √ ↔ √ [18] I

Escitalopram $ I ↔ √ ↔ √ ↔ √ [19] I

Esomeprazole magnesium $ I ↑ ↓ √ ↓ √ [20] I

Ethinylestradiol $ I ↑ ↓ √ ↔ √ [21] I

14

Everolimus $ I ↑ ↓ √ ↔ √ [22] I

Fluvastatin sodium I ↑ ↓ ↓ [23] II-1

Fluvoxamine $ I ↔ ↔ √ ↔ √ [24] I

Hydrocodone I ↓ ↑ ↔ [25] I

Hydrocortisone I ↑ √ ↓ √ [26] II-1

Hydromorphone $ I ↓ ↑ √ ↔ √ [27] I

Hydroxychloroquine sulfate $ I ↔ √ ↔ √ ↔ √ [28] I

Idarubicin I ↓ ↑ [29] I

Imipramine $ I ↔ √ ↔ √ ↔ √ [30] I

Isoniazid $ I ↑ √ ↓ √ ↔ √ [31] I

Isosorbide mononitrate $ I ↔ √ ↔ √ ↔ √ [32] I

Labetalol $ I ↔ √ ↔ √ ↑ √ [33] I

Letrozole $ I ↑ ↓ √ ↔ √ [34] II-1

Melphalan I ↔ ↓ ↓ √ [35] I

Metoprolol $ I ↔ √ ↔ √ ↔ √ [36] I

Metronidazole $ I ↑ √ ↓ √ ↓ √ [37] I

Midazolam hydrochloride $ I ↑ √ ↓ √ ↓ √ [38] I

Minocycline hydrochloride I ↑ √ ↓ √ ↓ √ [39] II-1

Mirtazapine $ I ↑ √ ↔ √ ↔ √ [40] I

Misoprostol $ I ↑ √ ↓ √ ↔ √ [41] I

Morphine hydrochloride $ I ↔ √ ↔ √ ↑ √ [42] I

Nicardipine I ↑ ↓ ↓ [43] I

Norethindrone $ I ↔ ↓ √ ↑ √ [21] I

Norgestimate $ I ↑ ↓ √ ↔ √ [44] I

Nortriptyline $ I ↔ √ ↔ √ ↔ √ [45] I

15

Omeprazole $ I ↔ √ ↔ √ [46] I

Ondansetron $ I ↔ √ ↔ √ ↑ √ [47] I

Oxprenolol $ I ↔ √ ↔ √ ↔ √ [48] II-1

Oxybutynin hydrochloride $ I ↔ √ ↑ √ ↔ √ [49] I

Oxycodone $ I ↔ √ ↓ √ ↑ √ [50] I

Pantoprazole sodium $ I ↓ ↔ √ ↔ √ [51] II-1

Paracetamol $ I ↑ √ ↓ √ ↓ √ [52] I

Paroxetine $ I ↔ √ ↔ √ ↔ √ [53] II-1

Pefloxacin $ I ↑ √ ↔ √ ↔ √ [54] I

Pentoxifylline $ I ↑ √ ↓ √ ↔ √ [55] II-1

Perindopril erbumine $ I ↔ √ ↔ √ ↔ √ [56] I

Primaquine $ I ↑ √ ↑ √ [57] I

Propantheline bromide I ↓ √ ↓ √ ↓ [58] I

Propranolol hydrochloride $ I ↔ √ ↑ √ ↑ √ [59] I

Propylthiouracil $ I ↔ √ ↔ √ ↔ √ [60] II-1

Pyrazinamide $ I ↔ √ ↔ √ ↔ √ [61] I

Rabeprazole sodium $ I ↑ √ ↔ √ ↔ √ [62] I

Ramipril $ I ↔ √ ↔ √ ↔ √ [63] I

Reboxetine I ↑ ↓ ↔ [64] II-1

Ribavirin I ↔ √ ↓ √ ↓ √ [65] I

Riluzole $ I ↑ √ ↓ √ ↓ √ [66] I

Rimantadine hydrochloride $ I ↔ √ ↔ √ ↔ √ [67] I

Rizatriptan $ I ↑ √ ↔ √ ↑ √ [68] I

Ropinirole $ I ↑ √ ↓ √ ↓ √ [69] I

Selegiline $ I ↔ √ ↑ √ ↑ √ [70] I

16

Sertraline hydrochloride I ↓ ↑ ↔ √ [71] I

Sibutramine I ↑ ↓ ↔ [72] I

Sildenafil $ I ↑ √ ↓ √ ↓ √ [73] I

Solifenacin succinate $ I ↔ √ ↔ √ ↔ √ [74] I

Sunitinib malate $ I ↔ √ ↔ √ ↔ √ [75] I

Tacrine $ I ↑ √ ↓ √ ↓ √ [76] I

Tenoxicam $ I ↑ √ ↓ √ ↔ √ [77] II-1

Terazosin $ I ↑ √ ↓ √ ↔ √ [78] I

Theophylline I ↑ √ ↓ √ ↔ √ [79] II-1

Ticlopidine $ I ↔ √ ↔ √ ↑ √ [80] I

Timolol $ I ↔ √ ↔ √ ↔ √ [81] I

Tolterodine $ I ↑ √ ↑ √ [82] I

Urapidil I ↑ ↑ ↔ [83] II-1

Valproic acid $ I ↔ √ ↔ √ [84] II-1

Vardenafil $ I ↑ ↓ √ ↔ √ [85] I

Venlafaxine hydrochloride $ I ↑ √ ↔ √ ↔ √ [86] I

Verapamil hydrochloride I ↑ √ ↔ √ ↔ √ [87] I

Vinorelbine tartrate $ I ↔ √ ↔ √ ↔ √ [88] I

Zidovudine I ↑ √ ↓ √ [89] I

Zolmitriptan $ I ↔ √ ↔ √ ↔ √ [90] I

Zolpidem tartrate I ↑ ↓ ↓ [91] II-1

Acitretin $ II ↔ √ ↑ √ ↑ √ [92] I

Albendazole $ II ↑ ↑ √ ↑ √ [93] II-1

Amiodarone hydrochloride $ II ↓ √ ↑ √ ↑ √ [94] I

Aprepitant $ II ↔ √ ↔ √ ↔ √ [95] I

17

Armodafinil II ↑ ↔ ↔ [96] I

Artemether $ II ↑ ↑ √ ↑ √ [97] I

Atazanavir sulfate II ↑ [98] II-1

Atorvastatin calcium $ II ↑ ↓ √ ↔ √ [99] I

Bevantolol $ II ↑ √ ↔ √ ↔ √ [100] I

Bicalutamide $ II ↔ √ ↑ √ ↔ √ [101] I

Bosentan $ II ↑ ↑ √ ↔ √ [102] I

Buspirone $ II ↔ √ ↔ √ ↑ √ [103] II-1

Cabergoline $ II ↔ √ ↔ √ ↔ √ [104] I

Carbamazepine $ II ↔ √ ↑ √ ↔ √ [105] I

Carvedilol $ II ↔ √ ↔ √ ↔ √ [106] I

Cefpodoxime proxetil $ II ↔ √ ↑ √ ↑ √ [107] I

Cilostazol $ II ↑ ↑ √ ↑ √ [108] I

Cinacalcet $ II ↓ ↑ √ ↑ √ [109] I

Clofazimine II ↓ ↑ ↑ [110] II-1

Clozapine $ II ↔ √ ↔ √ ↔ √ [111] I

Cyclosporine $ II ↔ √ ↔ √ ↔ √ [112] I

Danazol $ II ↔ √ ↑ √ ↑ √ [113] I

Darunavir $ II ↑ ↑ √ ↑ √ [114] I

Desloratadine $ II ↔ √ ↔ √ [115] I

Dicoumarol II ↑ √ [116] II-1

Ebastine $ II ↔ √ ↑ √ ↑ √ [117] I

Erlotinib hydrochloride $ II ↑ ↑ √ ↑ √ [118] I

Etravirine $ II ↑ ↓ √ ↓ √ [119] I

Febuxostat $ II ↑ √ ↓ √ ↓ √ [120] I

18

Fenofibrate $ II ↑ ↔ √ ↔ √ [121] I

Flurbiprofen $ II ↑ √ ↑ √ ↑ √ [122] I

Gefitinib $ II ↔ ↑ √ ↑ √ [123] I

Glipizide $ II ↑ √ ↔ √ ↔ √ [124] II-1

Griseofulvin $ II ↔ √ ↑ √ ↔ √ [125] II-1

Ibuprofen $ II ↔ √ ↑ √ ↔ √ [122] I

Iloperidone II ↔ √ ↔ √ ↔ √ [126] I

Indinavir sulfate $ II ↑ √ ↓ √ ↓ √ [127] I

Indobufen $ II ↑ ↓ √ ↓ √ [128] I

Indomethacin $ II ↑ √ ↔ √ ↔ √ [129] I

Irbesartan $ II ↔ √ ↔ √ ↔ √ [130] I

Isradipine $ II ↑ √ ↔ √ [131] II-1

Itraconazole $ II ↔ √ ↑ √ ↑ √ [132] I

Ketoconazole $ II ↑ √ ↔ √ ↔ √ [133] I

Ketoprofen $ II ↑ √ ↓ √ ↔ √ [134] II-1

Lamotrigine $ II ↑ ↓ √ ↓ √ [135] I

Lansoprazole $ II ↑ √ ↓ √ ↓ √ [136] I

Lapatinib ditosylate $ II ↑ √ ↑ √ ↑ √ [137] I

Loratadine $ II ↑ ↑ √ ↑ √ [138] I

Losartan potassium $ II ↑ ↔ √ ↑ √ [139] I

Mefenamic acid $ II ↔ √ ↔ √ ↔ √ [140] II-1

Mefloquine $ II ↓ √ ↑ √ ↑ √ [141] I

Meloxicam $ II ↓ ↑ √ ↔ √ [142] I

Mercaptopurine II ↔ √ ↔ √ [143] II-1

Mycophenolate mofetil $ II ↔ √ ↓ √ ↔ √ [144] II-1

19

Nabumetone II ↑ √ ↑ √ [145] I

Nateglinide $ II ↔ √ ↓ √ ↔ √ [146] I

Nefazodone $ II ↔ √ ↔ √ ↓ √ [147] II-1

Nelfinavir $ II ↑ √ ↑ √ [148] I

Nifedipine $ II ↓ √ ↔ √ [149] I

Nilotinib $ II ↑ √ ↑ √ [150] II-1

Nilvadipine $ II ↑ √ ↔ √ ↔ √ [151] I

Nimesulide $ II ↔ √ ↓ √ ↔ √ [152] II-1

Nitrazepam $ II ↑ √ ↔ √ ↔ √ [153] I

Nitrendipine II ↑ √ ↓ √ ↓ √ [154] II-1

Norethindrone acetate $ II ↑ ↓ √ ↑ √ [21] I

Oxaprozin $ II ↔ √ ↔ √ ↔ √ [155] II-1

Oxcarbazepine $ II ↑ ↑ √ ↑ √ [156] I

Phenytoin sodium $ II ↔ √ ↑ √ ↑ √ [157] II-1

Pioglitazone $ II ↑ ↔ √ ↔ √ [158] I

Posaconazole $ II ↑ √ ↑ √ [159] I

Praziquantel $ II ↔ √ ↑ √ ↑ √ [160] I

Prednisone $ II ↔ √ ↔ √ ↔ √ [161] II-1

Propafenone hydrochloride $ II ↓ √ ↑ √ ↑ √ [162] I

Propoxyphene napsylate $ II ↔ √ ↔ √ ↔ √ [2] II-1

Quazepam $ II ↔ √ ↑ √ ↑ √ [153] I

Quinapril $ II ↑ √ ↔ √ ↔ √ [163] I

Raltegravir potassium $ II ↔ √ ↑ √ ↑ √ [164] I

Rifabutin $ II ↑ √ ↔ √ ↔ √ [165] I

Rifampin $ II ↑ √ ↓ √ ↔ √ [166] I

20

Rufinamide $ II ↓ ↑ √ ↑ √ [167] I

Saquinavir methanesulfonate II ↑ ↑ ↑ [168] I

Sirolimus $ II ↑ √ ↓ √ ↑ √ [169] I

Spironolactone $ II ↔ √ ↑ √ ↑ √ [170] I

Tacrolimus $ II ↑ √ ↓ √ ↓ √ [171] I

Tegaserod maleate $ II ↓ √ ↓ √ ↓ √ [172] I

Telithromycin $ II ↔ ↔ √ ↔ √ [173] I

Terbinafine II ↑ √ ↔ √ ↔ √ [174] I

Terfenadine $ II ↑ √ ↔ √ ↔ √ [175] I

Thalidomide $ II ↑ √ ↔ √ ↔ √ [176] I

Tibolone II ↔ √ ↔ √ [177] I

Tipranavir $ II ↑ √ ↑ √ ↑ √ [178] II-1

Tizanidine $ II ↑ √ ↓ √ ↓ √ [179] I

Tolbutamide $ II ↔ √ ↔ √ ↔ √ [180] II-1

Tolvaptan II ↑ ↑ √ ↑ √ [181] I

Triclabendazole $ II ↑ √ ↑ √ ↑ √ [182] II-1

Voriconazole $ II ↑ √ ↓ √ ↓ √ [183] I

Zileuton $ II ↔ √ ↑ √ ↔ √ [184] I

Ziprasidone hydrochloride $ II ↔ √ ↑ √ ↑ √ [185] I

Adefovir dipivoxil III ↑ √ [186] I

Albuterol $ III ↑ √ ↓ √ ↔ √ [187] I

Almotriptan III ↔ √ ↔ √ ↔ √ [188] II-1

Amoxicillin $ III ↑ √ ↔ √ ↔ √ [189] I

Ampicillin $ III ↑ √ ↔ √ ↓ √ [189] I

Atenolol $ III ↓ √ ↔ √ ↓ √ [190] I

21

Azithromycin III ↑ ↔ √ [191] I

Bendroflumethiazide $ III ↔ √ ↔ √ ↔ √ [192] II-1

Bisoprolol fumarate III ↔ ↔ ↔ √ [193] II-1

Bumetanide $ III ↑ √ ↓ √ ↔ √ [194] I

Captopril $ III ↑ √ ↓ √ ↓ √ [195] I

Cefaclor $ III ↑ √ ↓ √ ↔ √ [196] II-1

Cephradine III ↑ ↓ ↔ [197] I

Chloroquine $ III ↔ ↑ √ ↑ √ [198] II-1

Cimetidine $ III ↔ ↔ ↔ [263] I

Clavulanic acid $ III ↔ √ ↔ √ ↔ √ [200] I

Cycloserine $ III ↑ √ ↓ √ ↔ √ [201] I

Desmopressin $ III ↑ √ ↓ √ ↓ √ [202] I

Desvenlafaxine $ III ↑ ↔ √ ↔ √ [203] I

Didanosine $ III ↔ √ ↓ √ ↓ √ [204] II-1

Digoxin $ III ↔ √ ↓ √ ↔ √ [205] I

Doxycycline $ III ↑ √ ↓ √ ↓ √ [206] II-1

Emtricitabine $ III ↔ √ ↔ √ [207] I

Entecavir $ III ↑ √ ↓ √ ↓ √ [208] I

Ethambutol $ III ↔ √ ↔ √ ↔ √ [209] I

Etoposide $ III ↔ √ ↔ √ [210] I

Famotidine $ III ↔ √ ↔ √ ↔ √ [211] I

Fexofenadine $ III ↑ √ ↓ √ ↓ √ [212] I

Fluconazole $ III ↔ √ ↔ √ ↔ √ [132] I

Fosfomycin tromethamine $ III ↔ √ ↓ √ ↔ √ [213] II-1

Gabapentin III ↔ √ ↑ √ ↔ √ [214] I

22

Ganciclovir sodium $ III ↑ √ ↑ √ ↑ √ [215] I

Hydrochlorothiazide $ III ↔ √ ↔ √ ↑ √ [216] II-1

Lamivudine $ III ↑ √ ↓ √ ↔ √ [217] II-1

Leucovorin $ III ↑ √ ↑ √ ↑ √ [218] I

Levetiracetam $ III ↔ √ ↔ √ ↔ √ [219] I

Levofloxacin $ III ↑ √ ↔ √ ↔ √ [220] I

Lisinopril $ III ↔ √ ↔ √ ↔ √ [221] I

Lomefloxacin $ III ↑ √ ↔ √ ↔ √ [222] I

Metformin $ III ↑ √ ↓ √ ↓ √ [223] I

Methotrexate $ III ↑ √ ↔ √ ↔ √ [224] I

Metoclopramide $ III ↔ √ ↔ √ ↔ √ [225] I

Miglustat $ III ↑ ↓ √ ↔ √ [226] I

Moxifloxacin hydrochloride $ III ↑ ↓ √ ↔ √ [227] I

Nadolol III ↓ √ ↓ √ [228] I

Nizatidine III ↔ √ ↔ √ ↔ √ [229] I

Ofloxacin $ III ↑ √ ↓ √ ↔ √ [230] II-1

Penicillamine $ III ↓ √ ↓ √ ↓ √ [231] I

Pirenzepine $ III ↓ √ ↓ ↓ √ [232] I

Pramipexole $ III ↑ √ ↔ √ [233] I

Procainamide $ III ↔ √ ↔ √ ↔ √ [234] II-1

Pseudoephedrine $ III ↔ √ ↑ √ ↔ √ [138] I

Pyridostigmine III ↑ ↔ √ [235] II-1

Ranitidine $ III ↔ √ ↔ √ ↔ √ [236] II-1

Risedronate III ↑ ↓ ↓ [237] I

Saxagliptin $ III ↑ ↔ √ ↑ √ [238] I

23

Sitagliptin III ↔ √ ↔ √ ↔ √ [239] I

Sotalol $ III ↔ √ ↓ √ ↓ √ [240] II-1

Stavudine $ III ↑ √ ↓ √ ↔ √ [241] I

Sulpiride $ III ↔ √ ↔ √ ↓ √ [242] I

Talinolol $ III ↔ √ ↑ √ ↓ √ [243] I

Tenofovir disoproxil $ III ↑ √ ↔ √ ↑ √ [244] I

Tetracycline hydrochloride $ III ↔ √ ↓ √ ↓ √ [39] II-1

Topiramate $ III ↑ √ ↓ √ ↔ √ [245] I

Topotecan $ III ↑ √ ↔ √ ↔ √ [246] I

Vigabatrin $ III ↔ √ ↔ √ ↔ √ [247] I

Zalcitabine $ III ↑ √ ↓ √ ↓ √ [248] I

Acyclovir $ IV ↔ √ ↓ √ ↓ √ [249] II-1

Atovaquone IV ↓ ↑ ↑ √ [250] I

Cefixime $ IV ↑ √ ↔ √ ↔ √ [251] I

Cefprozil $ IV ↔ √ ↔ √ ↔ √ [196] I

Chlorothiazide IV ↑ ↑ ↑ √ [252] I

Cinoxacin $ IV ↔ √ ↓ √ ↔ √ [253] II-1

Ciprofloxacin $ IV ↔ √ ↔ √ ↔ √ [254] I

Enoxacin $ IV ↔ √ ↔ √ ↔ √ [255] I

Eprosartan $ IV ↑ √ ↓ √ ↓ √ [256] I

Erythromycin stearate $ IV ↔ √ ↓ √ ↓ √ [257] I

Fleroxacin $ IV ↑ √ ↓ √ ↓ √ [258] I

Furosemide $ IV ↑ ↓ ↔ √ [259] I

Lenalidomide $ IV ↑ √ ↓ √ ↓ √ [260] I

Norfloxacin IV ↔ √ ↓ √ ↓ √ [261] II-1

24

Roxithromycin $ IV ↑ √ ↓ √ ↓ √ [262] I

Level (of Evidence) (Wikipedia): I: obtained from at least one properly designed randomized controlled trial; II-1: obtained from well-designed controlled trials without

randomization; II-2: obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group; II-3: obtained from multiple

time series designs with or without the intervention; III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

25

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