Drugs Involved in Significant Pharmacokinetic Drug-Drug Interactions in 2015 This table lists drugs which are demonstrated (or predicted convincingly) to be involved in pharmacokinetic drug-drug interaction (DDI) at therapeutic doses in human associated with pH change, chelate formation Akihiro Hisakaa, Yoshiyuki Ohnob, Hiroshi Suzukib, Kazuya Maedac, Yuichi Sugiyamad in gastrointestinal tract or with alternations in activity of drug metabolizing enzymes and transporters. Most of drugs selected in this table are approved and frequently used in Japanese market as of Jan 2015. The a pharmacokinetic theory suggests that simultaneous oral intake of drugs(otherwise specified) in this table (such as a substrate and an inhibitor for the same enzyme) will cause significant pharmacokinetic DDI. The selection Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University of drugs in this table is based on open information and mostly described in refs 1) and 2) for CYP related DDIs with an analysis of alert classification of DDI in the product labeling. The selection of drugs for transporter b Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo related DDIs is described in refs 3) and 4). Please note that classification of drugs in this table is not conclusive and may be incomplete. Drugs which are not listed in this table may also cause serious DDIs, including c Graduate School of Pharmaceutical Sciences, The University of Tokyo pharmacodynamic DDIs. In clinical settings, appropriate cares must be taken for all possible DDIs. d Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN

Mechanism of DDI and Category 1) Victim Drugs of DDI Blood Level Increasing Drugs Blood Level Reducing Drugs Genetic Variation in Japanese

Interrupting absorption by pH ★ Antiretrovirals: Atazanavir(ATV), Saquinavir(SQV), Rilpivirine(RPV), Indinavir(IDV), Is DDI avoidable by adjusting timing of dose? Proton-pump inhibitors: Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole elevation Delavirdine Histamine H -antagonists: Famotidine, Ranitidine, Cimetidine, Roxatidine, Nizatidine, DDIs of proton-pump inhibitors are unavoidable due to their durative 2 ★ Antineoplastic agents(oral drug): Gefitinib, Dasatinib, Erlotinib, Pazopanib, Nilotinib Lafutidine Azoles: Itraconazole(except for oral liguid) pharmacological action. For other drugs, longer interval between the Antacids: Aluminium Hydroxide Magnesium Hydroxide preparations ★ doses is better in order to reduce significance of DDI. ・ pH change and chelate formation Interrupting absorption by ★ Antiretrovirals: Dolutegravir Is DDI avoidable by adjusting timing of dose? Antacids(for Cefdinir, blue): Aluminium Hydroxide・Magnesium Hydroxide preparations, in gastrointestinal formation of chelate ★Quinolones: Ciprofloxacin, Sitafloxacin, Tosufloxacin, Garenoxacin, Moxifloxacin, Sucralfate Hydrate, Dried Aluminium Hydroxide Gel, Levofloxacin When cefdinir needs to be used with iron preparations, iron preparations Synthetic Aluminum Silicate, Magnesium Hydroxide, Magnesium Oxide tract should be administered more than 3hr later than dose of cefdinir. ★ Tetracyclines: Doxycycline, Minocycline Iron preparations(for Cefdinir, bold red): Ferrous Citrate, Soluble Ferric pyrophosphate, Cephalosporins: Cefdinir Administration of multivalent cations should be avoided within 4hr Iron(II) Sulfate ★ before and after dose of eltrombopag and it should be administered in Hematopoietic agents: Eltrombopag Phosphate-removing agents(not defined for Cefdinir): Lanthanum Carbonate Hydrate, the fasting state. Other interacting drugs should be administered more Ferric citrate, Calcium Carbonate than 4hr before or 2hr after administration of "victim drugs".

In human, 57 genes of cytochrome P450 (CYP) are recognized. Among them, 23 species are belong to CYP1−3 families which are significantly selectivity with P-glycoprotein, a typical efflux transporter. In general, inhibition of CYP potentiates both pharmacological and adverse actions of a involved in drug metabolism. CYP3A4 is the most important drug metabolizing enzyme and mediates metabolism of approximately half of drugs in drug, and induction of CYP reduces them. However, when metabolite(s) are pharmacologically active, the situation may be reversed. Usually, degree the market. CYP3A4 is expressed in the liver and intestine, and other CYPs are expressed predominantly in the liver. CYP3A4 often shares substrate of DDI is more evident when victim drugs are given orally compared with other route of administration. Inhibition and induction of Skeletal muscle relaxants: Tizanidine SSRIs: Fluvoxamine Anticonvulsants: Phenytoin CYP1A2 Melatonin receptor agonists: Ramelteon, Melatonin Quinolones: Ciprofloxacin, Enoxacin, Clinafloxacin Others: smoking intermediate 1% ★ Xanthine derivatives: Caffeine, Theophylline NSAIDs: Rofecoxib extensive 99% SNRIs: Duloxetine Contraceptives: (progesterone and ethinylestradiol) Antifibrotic agents: Pirfenidone Antiarrhythmics: Mexiletine Nonergot-derivative dopamine receptor agonists: Ropinirole Vitiligo therapeutic agents: Methoxsalen Atypical antipsychotics: Clozapine, Olanzapine Muscle relaxant: Idrocilamide 5-HT3 inhibitors: Alosetron, Ramosetron Acetylcholinesterase inhibitors: Tacrine Induction of CYP2B6 DNRIs: Bupropion Antiretrovirals: Efavirenz(EFV) intermediate 21% Antiretrovirals: Efavirenz(EFV) extensive 79% Inhibition of CYP2C8 ★ Antidiabetic agents: Repaglinide, Pioglitazone Antilipemic agents: Gemfibrozil※ Antituberculosis agents: Rifampicin extensive 100% Leukotriene-receptor antagonists: Montelukast Iron chelating agents: Deferasirox Immunosuppressive agents: Cyclosporin Inhibition and induction of ★ Anticoagulants: Warfarin Fluorinated pyrimidine antagonist2): TS-1※, UFT※, Tegafur※, Fluorouracil※, Antituberculosis agents: Rifampicin CYP2C9 ★ Antidiabetic agents: Glimepiride, Tolbutamide, Glibenclamide, Nateglinide Doxifluridine※, Capecitabine※, Carmofur※ Anticonvulsants: Phenobarbital, Carbamazepine intermediate 4% ★ Anticonvulsants: Phenytoin Azoles: Miconazole, Fluconazole Antiemetics: Aprepitant extensive 96% NSAIDs: Diclofenac, Celecoxib, Ibuprofen Sulfonamides: Sulfaphenazole Antilipemic agents: Fluvastatin Antiarrhythmics: Amiodarone Antigout agents: Bucolome Immunosuppressive agents: Cyclosporin Inhibition and induction of ★ Azoles: Voriconazole SSRIs: Fluvoxamine, Fluoxetine Antituberculosis agents: Rifampicin CYP2C19 Proton-pump inhibitors: Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole Platelet-aggregation inhibitors: Ticlopidine※ Antiretrovirals: Ritonavir(RTV) poor 16% ★ Antiepileptic agents: Clobazam, S-Mephenytoin Azoles: Voriconazole, Fluconazole intermediate 48% Benzodiazepines: Diazepam, Etizolam Diuretics: Tienilic acid extensive 36% Platelet-aggregation inhibitors: Clopidogrel3) Antidepressants: Moclobemide SSRIs: Sertraline, Escitalopram Inhibition of CYP2D6 Antitussives: Dextromethorphan SSRIs: Paroxetine※, Fluoxetine, Escitalopram poor 3% Genitourinary smooth muscle relaxants: Tolterodine 5) Allylamine antifungal agents: Terbinafine *10/*10 14%4) Opiate agonists: Tramadol 3) Antiarrhythmics: Quinidine intermediate 35% SNRIs: Atomoxetine Calcium receptor agonists: Cinacalcet extensive 48% ★ Antiarrhythmics: Encainide, Propafenone, Flecainide Genitourinary smooth muscle relaxants: Mirabegron6) Cytochrome 3) P450 (CYP) ★ Antineoplastic agents(oral drug): Tamoxifen SNRIs: Duloxetine Antidepressants: Trimipramine, Desipramine, Nortriptyline, Maprotiline, Venlafaxine, DNRIs: Bupropion Doxepin, Amitriptyline, Imipramine, Clomipramine NSAIDs: Celecoxib β-adrenergic blocking agents: Metoprolol, Nebivolol, Timolol, Propranolol Antineoplastic agents: Dacomitinib Antipsychotics: Perphenazine Antidepressants: Moclobemide 5-HT3 inhibitors: Tropisetron Inhibition and induction of ★ Benzodiazepines: Triazolam, Midazolam, Alprazolam Azoles: Itraconazole, Voriconazole, Ketoconazole, Posaconazole, Antituberculosis agents: Rifampicin, Rifabutin CYP3A7) ★ Immunosuppressive agents: Everolimus, Sirolimus, Tacrolimus Miconazole, Fluconazole Anticonvulsants: Phenobarbital, Phenytoin, Carbamazepine intermediate 2% Antilipemic agents: Simvastatin, Lovastatin, Atorvastatin Antiretrovirals: Ritonavir(RTV)※, Indinavir(IDV)※, Cobicistat, Antiretrovirals: Etravirine(ETR), Efavirenz(EFV) extensive 98% Calcium-channel blocking agents: Nisoldipine, Felodipine, Azelnidipine Nelfinavir(NFV)※, Saquinavir(SQV)※, Atazanavir(ATV)※, Others: St.John's wort Antipsychotics: Blonanserin, Quetiapine, Lurasidone Fosamprenavir(FPV), Amprenavir(APV) Psychostimulants: Modafinil ★ Antipsychotics(Risk of LQTS): Pimozide HCV protease inhibitors: Telaprevir, Boceprevir Endothelin-receptor antagonists: Bosentan PDE-5 inhibitors: Vardenafil, Sildenafil, Tadalafil Macrolides: Troleandomycin※, Clarithromycin※, Erythromycin※ Antidepressants: Buspirone Calcium-channel blocking agents: Diltiazem※, Verapamil※ ★ Antineoplastic agents(oral drug): Dasatinib Antidepressants: Nefazodone※ ★ Antiretrovirals: Maraviroc(MVC), Darunavir(DRV), Indinavir(IDV), Lopinavir(LPV), Fruit juice: Grapefruit juice※ Saquinavir(SQV), Tipranavir(TPV), Rilpivirine(RPV) Antineoplastic agents: Imatinib※, Crizotinib ★ Anticoagulants: Rivaroxaban Antiemetics: Aprepitant, Casopitant Platelet-aggregation inhibitors: Ticagrelor Quinolones: Ciprofloxacin ★ Antiarrhythmics: Dronedarone Immunosuppressive agents: Cyclosporin Vasopressin V2 receptor antagonists: Conivaptan, Tolvaptan Benzodiazepines: Tofisopam Mineralocorticoid receptor antagonists: Eplerenone Vasopressin V2 receptor antagonists: Conivaptan Selective serotonin agonists: Eletriptan Antiarrhythmics: Dronedarone Corticosteroids(inhaled drug): Budesonide, Fluticasone Adenosine A2A receptor antagonists: Istradefylline Antiemetics: Aprepitant Opiate agonists: Alfentanil Drug names are colored in red, orange, blue or green based on classification of DDI potential in the order of extensiveness. Drug categories marked with a Antigout agents: Colchicine8) star(★ ) indicate that more noticeable clinical risks would be arisen for these drugs compared with those without a star. Genitourinary smooth muscle relaxants: Darifenacin Red: AUC increase to more than 5-fold or AUC decrease to less than 1/5 has been reported in principle. Orange: AUC increase to more than 3-fold or AUC decrease to less than 1/3 has been reported in principle. Blue: AUC increase to more than 1.5~2-fold or AUC decrease to less than 1/2~1/1.5 has been reported in principle. Green: In transporter-related DDIs, AUC change of less than 1.5-fold has been reported or DDI is predicted from nonclinical information. For RED-RED combinations, AUC of "victim drugs" would be increased at least 3-fold, and in extensive situations, more than 10-fold when co-administered with "Blood level increasing drugs". In a similar manner, 2−5-fold increase is anticipated for RED-ORANGE combinations, 1.5~3-fold increase is anticipated for RED-BLUE and ORANGE-ORANGE combinations, and less than 2-fold increase is anticipated for ORANGE-BLUE and BLUE-BLUE combinations. These predictions are based on pharmacokinetic analyses applied to DDIs associated with alternation in activity of drug metabolizing enzymes, but its applicability to transporter-mediated and other mechanisms based DDIs is yet unknown. For cytochrome P450-mediated DDIs, bold red, red, orange and blue names correspond to contribution ratio (CR) and inhibition ratio (IR) of equal to or more than 0.9, 0.8, 0.7, and 0.5, and correspond to increase in clearance (IC) of equal to or more than 5, 3, 1, and less than 1.0, respectively, in principle (ref 1).

Conjugation reactions include glucuronidation, sulfation, glutathione conjugation etc. Each reaction is usually mediated by multiple enzyme species of unchanged drug may not be influenced by alternation in conjugation metabolism. In this situation, levels of metabolite would be altered due to DDI which are expressed in the intestine and liver predominantly. In general, inhibition of conjugation potentiates both the pharmacological and adverse associated with conjugation reaction. actions of a drug, and induction of conjugation reduces them. However, since conjugation takes place often after phase-1 oxidative metabolism, level Inhibition or induction of ★ Anticonvulsants: Valproate{2B7}9), Lamotrigine{1A4} Antigout agents: Probenecid{1A} Carbapenems9): Panipenem, Meropenem, Imipenem glucuronide conjugation enzyme ★ Antiretrovirals: Zidovudine(AZT){2B7} Azoles: Fluconazole{2B7} Antituberculosis agents: Rifampicin Conjugation Representative molecular species of ★ Benzodiazepines: Lorazepam{1A3, 2B15} Antiretrovirals: Atazanavir(ATV){1A1} Antiretrovirals: Ritonavir(RTV) UGT are shown in {}. However, multiple ★ Immunosuppressive agents: Mycophenolate mofetil{1A9} Anticonvulsants: Valproate{1A1} Contraceptives: Ethinylestradiol species are frequently involved in the ★ Antineoplastic agents(injection drug): Irinotecan{1A1}10) Antineoplastic agents(oral drug): Sorafenib{1A1} Anticonvulsants: Phenobarbital, Phenytoin, Carbamazepine same reaction and the specification is NSAIDs: Indomethacin{2B7}, Ketoprofen{1A, 2B}, Naproxen{1A3} not conclusive. Contraceptives: Ethinylestradiol{1A1} Iron chelating agents: Deferasirox{1A1, 1A3} Inhibition or induction P−glycoprotein (P-gp) is expressed at the luminal membrane of enterocytes in the intestine and suppress absorption of drugs. in general and thus leads to an increase in pharmacological and adverse actions with increased blood drug concentration. of MDR1 (P-glycoprotein)7) involved In addition, P-gp is expressed at the bile canalicular membrane in the liver and at the tubular luminal membrane in the kidney P-gp is also expressed in the brain and protects the brain against exposure of xenobiotics, thus inhibition of P-gp may increase in restriction of intestinal and mediates biliary and renal excretion of drugs. Inhibition of P-gp promotes intestinal absorption and delays in excretion, invasion of drugs into the brain. absorption and brain penetration Antiretrovirals: Saquinavir(SQV), Indinavir(IDV) Antiretrovirals: Ritonavir(RTV), Nelfinavir(NFV) Antituberculosis agents: Rifampicin intermediate ★ 11) Antineoplastic agents(injection drug): Paclitaxel, Docetaxel Azoles: Itraconazole, Ketoconazole Others: St.John's wort (C3435T homozygotes) : 18% ★ ★ Cardiac glycosides: Digoxin Macrolides: Erythromycin, Clarithromycin Anticonvulsants: Carbamazepine ★ Immunosuppressive agents: Cyclosporin, Tacrolimus Immunosuppressive agents: Cyclosporin ★ Anticoagulants: Dabigatran Etexilate, Edoxaban, Rivaroxaban Antiarrhythmics: Quinidine Renin inhibitors: Aliskiren Calcium-channel blocking agents: Verapamil Antidiarrhea agents: Loperamide Ketolides: Telithromycin β-adrenergic blocking agents: Celiprolol, Talinolol Antilipemic agents: Lovastatin Antihistamines: Fexofenadine Vasopressin V2 receptor antagonists: Tolvaptan Calcium-channel blocking agents: Verapamil SSRI: Fluvoxamine Inhibition of BCRP involved BCRP is expressed at the luminal membrane of enterocytes in the intestine and suppresses absorption of drugs. In addition, general and thus leads to an increase in pharmacological and adverse actions with increased blood drug concentration. BCRP in restriction of intestinal BCRP is expressed at the bile canalicular membrane in the liver and at the tubular luminal membrane in the kidney and is also expressed in the brain and in the mammary gland. absorption mediates biliary and renal excretion of drugs. Inhibition of BCRP promotes intestinal absorption and delays in excretion, in reduced function Antineoplastic agents: Diflomotecan, Nogitecan(Topotecan) Hematopoietic agents: Eltrombopag (C421A homozygotes): 12% ★ ★ Antineoplastic agents / antirheumatic agents: Methotrexate Others: Curcumin Sulfonamides: Salazosulfapyridine Antilipemic agents: Rosuvastatin Inhibition of OATPs12) involved OATPs are expressed at the luminal membrane of enterocytes in the intestines and mediate absorption of drugs into the blood. in intestinal absorption Therefore, inhibition of OATPs may reduce blood drug concentration and pharmacological actions of substrate drugs. reduced function -adrenergic blocking agents: Celiprolol, Talinolol, Atenolol, Acebutolol Fruit juice: Grapefruit juice, Orange juice, Apple juice (OATP2B1 C1457T homozygotes) β Antihistamines: Fexofenadine : 13% Renin inhibitors: Aliskiren ★ Antineoplastic agents: Etoposide Leukotriene-receptor antagonists: Montelukast Inhibition and induction OATP1B1 and OATP1B3 are expressed at the basolateral membrane in hepatocytes and mediate hepatic uptake of drugs. of OATP1B1 and/or OATP1B3 Inhibition of OATP1B1/1B3 may increase blood concentrations and pharmacological/adverse actions of substrate drugs. involved in uptake into the liver 13) Antilipemic agents: Pravastatin, Atorvastatin, Rosuvastatin, Simvastatin, Pitavastatin, Immunosuppressive agents: Cyclosporin Antituberculosis agents: Rifampicin(repeated-dose administration) Transporter increased function 13) 11) Ezetimibe, Fluvastatin, Cerivastatin Antituberculosis agents: Rifampicin(single-dose administration) Antiretrovirals: Efavirenz(EFV) (OATP1B1 A388G homozygotes) : 40% HCV protease inhibitors: Asunaprevir, Vaniprevir, Simeprevir HCV protease inhibitors: Telaprevir, Simeprevir, Asunaprevir, Vaniprevir reduced function Angiotensin receptor antagonists: Fimasartan, Valsartan, Olmesartan, Telmisartan Antilipemic agents: Gemfibrozil (OATP1B1 T521C homozygotes): 3% Endothelin-receptor antagonists: Bosentan, Ambrisentan, Atrasentan Macrolides: Clarithromycin ★ Antidiabetic agents: Glibenclamide, Repaglinide, Nateglinide Antiretrovirals: Atazanavir(ATV), Lopinavir(LPV), Darunavir(DRV), Antihistamines: Fexofenadine Tipranavir(TPV) ★ Antineoplastic agents(injection drug): Paclitaxel, Docetaxel Others: Quercetin Angiotensin-converting enzyme inhibitors: Temocapril, Enalapril Duretics: Torasemide ★ Antiretrovirals: Lopinavir(LPV) Inhibition of OAT1 OAT1 and OAT3 are expressed at the tubular basolateral membrane in the kidney and mediate renal excretion of drugs. and/or OAT3 involved Inhibition of OATs may increase blood concentrations and pharmacological/adverse actions of substrate drugs. in uptake into the kidney ★ Antineoplastic agents / antirheumatic agents: Methotrexate Antigout agents: Probenecid ★ Antiretrovirals: Zidovudine(AZT) NSAIDs: Indomethacin, Salicylic acid, Phenylbutazone ★ Nucleoside and nucleotide analogs: Adefovir, Ganciclovir, Cidofovir Antilipemic agents: Gemfibrozil NSAIDs: Ketorolac, Indomethacin, Ketoprofen, Naproxen, Tenoxicam Penicillins, Cephalosporins Quinolones: Levofloxacin, Ofloxacin, Ciprofloxacin Diuretics: Furosemide Neuraminidase inhibitors: Oseltamivir14) ★ Antidiabetic agents: Sitagliptin Angiotensin-converting enzyme inhibitors: Enalapril, Captopril Histamine H2-antagonists: Famotidine Inhibition of MATEs MATEs are expressed at the tubular luminal membrane in the kidney and mediate renal excretion of drugs. involved Inhibition of MATEs may increase blood concentrations and pharmacological/adverse actions of substrate drugs. MATEs are also expressed in the liver. in efflux from the kidney Histamine H2-antagonists: Cimetidine Histamine H2-antagonists: Cimetidine ★ Antidiabetic agents: Metformin Antiretrovirals: Dolutegravir15) ★ Antiarrhythmics: Procainamide, Pilsicainide, Dofetilide Diamino-pyrimidines: Trimethoprim Diuretics: Triamterene Antimalarial agents: Pyrimethamine β-adrenergic blocking agents: Pindolol Quinolones: Levofloxacin

※ Due to irreversible inhibition or analogous mechanism, several days would be required to reach the maximum inhibition and then also to cease the interaction. 11) In clinical studies and experiments, some discrepancies have been observed, which might be several reasons such as the use of different substrates. Therefore, information needs 1) Frequency of genetic variants described in this table, are estimated in Japanese population (poor: activity is deficient, intermediate: activity is approximately half of to be interpreted cautiously. extensive,extensive: normal activity). It should be noted that remarkable ethnic differences exist in frequency of genetic variants. Drug blood concentrations may increase in poor 12) Target transporters are yet unknown.Some literatures suggest involvement of OATP1A2 and OATP2B1. Recent reports demonstrated that genetic polymorphisms of OATP2B1 and intermediate metabolizers even in the absence of DDI. DDI in poor and intermediate metabolizers is complex and unknown so far. affected the pharmacokinetics of some drugs. 2) It has been reported that fluorouracils do not inhibit CYP2C9 directly in vitro, but decrease expression of CYP2C in vivo. 13) Rifampicin is an inhibitor of OATP1B1 and also a potent inducer of transporters including OATP1B1 and metabolizing enzymes at the same time. After a single dose, drug 3) Drugs are pharmacologically activated by metabolism. Therefore, co-administration with inhibitors can cause decrease in pharmacological/adverse actions, and co-administration concentrations may increase since inhibition is predominant. However, it has been reported that drug concentrations turn to decrease after multiple doses, because of the increase of inducers is vice versa. in hepatic uptake which is associated with induction of OATP1B1. Prediction of pharmacokinetics in the presence of both inhibitory and inductive DDI would be difficult. 4) Activity of CYP2D6 is usually reduced to approximately 1/5 of extensive metabolizer in *10 homozygotes. 14) Blood concentration of an active metabolite of oseltamivir is increased due to the decrease in renal clearance when probenecid is co-administered. 5) Clinical significance of associated DDIs is controversial, since metabolite(s) of tolterodine is also pharmacologically active. 15) OCT2 can also be inhibited at the clinical dose. 6) Observed with double dose comparing usual dosage. References: 7) Contributions of CYP3A4 and P-gp to the intestinal absorption of drugs are difficult to be separated due to the overlapping substrate and inhibitor specificities. Representative 1. Hisaka A, Ohno Y, Yamamoto T, and Suzuki H. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. inhibitors of CYP3A4 and P-gp are separately shown in this table. Pharmacol. Ther. 2010; 125: 230-48. 8) The degree of drug interaction would be increased when renal function is impaired. 2. Hisaka A, Kusama M, Ohno Y, Sugiyama Y, and Suzuki H. A proposal for a pharmacokinetic interaction significance classification system (PISCS) based on predicted drug 9) Mechanism of DDI between carbapenems and valproate is complex. Some reports suggest that it is due to inhibition of deconjugation of valproate glucuronide by carbapenems. exposure changes and its potential application to alert classifications in product labeling. Clin Pharmacokinet, 2009: 48: 653-66. No report suggests DDI between carbapenems and other substrates of UGT. 3. Maeda K, Shitara Y, Horie T, and Sugiyama Y. Web-based database as a tool to examine drug-drug interactions involving transporters in: "Enzyme- and transporter-based drug- 10) Irinotecan is transformed to the pharmacologically active SN-38 by carboxyesterase and simultaneously to an inactive metabolite by CYP3A4. Therefore, inhibition of CYP3A4 drug interactions" ed. by Pang KS, Rodrigues AD, and Peter RM, Springer, New York, pp. 387-414 (2010). causes an increase in blood drug concentration of SN-38. SN-38 is conjugated with glucuronic acid and then excreted into the bile. Inhibition of CYP3A4 metabolism of irinotecan, 4. Shitara Y, Sato H and Sugiyama Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol Toxicol 45: 689-723(2005). therefore, may cause adverse events such as neutropenia. PharmaTribune Vol.7 No.4 Suppl.2 (In press, 2015, original text in Japanese) Copyright 2015 Yuichi Sugiyama, et. al. Published by Medical Tribune, Inc., 2-1-30, Kudan Minami, Chiyoda-ku Tokyo 102-0074, Japan All rights reserved. No part of this table covered by the herein may be reproduced or used in any format in any form or by any means graphic, electronic, or mechanical, including, Vol.7 No.4 April, 2015 Suppl.2 photocopying, recording, taping, or information storage such as data base or retrieval systems without permission of the publisher.