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Drugs Involved in Significant Pharmacokinetic Drug-Drug Interactions in 2016
This table lists drugs those have been demonstrated or anticipated to be involved in pharmacokinetic drug-drug interactions (DDIs) at therapeutic doses in human, and caused by gastric pH changes, chelate formations or
alternations in activity of the drug metabolizing enzymes and transporters. Most of drugs selected in this table have been approved and are frequently used in Japanese market as of Oct 2016. The pharmacokinetic theory
suggests that simultaneous oral intake of drugs listed as a substrate and an inhibitor/inducer for the same enzyme in this table will cause significant pharmacokinetic DDI otherwise specified. The selection of drugs in this table
is based on open information (mostly in refs 1) and 2) for CYP related DDIs) with an analysis of alert classification of DDI in the product labeling. Drugs not listed in the draft Japanese guideline titled “Drug Interaction Guideline
for Drug Development and Labeling Recommendations (Final Draft)” are underlined. The selection of drugs for transporter 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 pharmacodynamic DDIs. In clinical settings, appropriate cares must be taken for all possible DDIs.
Category
pH change and
chelate formation
in gastrointestinal
tract
Mechanism of DDI and
Genetic Variation in Japanese1)
Victim Drugs of DDI
Interrupting absorption by pH
elevation
★A
ntiretrovirals: Atazanavir (ATV), Saquinavir(SQV), Rilpivirine (RPV), Indinavir(IDV),
Interrupting absorption by
formation of chelate
★Antiretrovirals: Dolutegravir
★Q uinolones: Ciprofloxacin, Sitafloxacin, Tosufloxacin, Garenoxacin, Moxifloxacin,
Delavirdine
★A
ntineoplastic agents(oral drug): Gefitinib, Dasatinib, Erlotinib, Pazopanib, Nilotinib
★A
zoles: Itraconazole(except for oral liguid)
Levofloxacin
★Tetracyclines: Doxycycline, Minocycline
★Cephalosporins: Cefdinir
Hematopoietic agents: Eltrombopag
Blood Level Increasing Drugs
Blood Level Reducing Drugs
Proton-pump inhibitors: Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole
Histamine H2-antagonists: Famotidine, Ranitidine, Cimetidine, Roxatidine, Nizatidine,
Lafutidine
Antacids: Aluminium Hydroxide・Magnesium Hydroxide preparations
Is DDI avoidable by adjusting timing of dose?
When cefdinir needs to be used with iron preparations, iron preparations
should be administered more than 3hr later than dose of cefdinir.
Administration of multivalent cations should be avoided within 4hr
before and after dose of eltrombopag and it should be administered in
the fasting state. Other interacting drugs should be administered more
than 4hr before or 2hr after administration of "victim drugs".
Antacids(for Cefdinir, blue): Aluminium Hydroxide・Magnesium Hydroxide preparations,
Sucralfate Hydrate, Dried Aluminium Hydroxide Gel,
Synthetic Aluminum Silicate, Magnesium Hydroxide, Magnesium Oxide
Iron preparations(for Cefdinir, bold red): Ferrous Citrate, Soluble Ferric pyrophosphate,
Iron(II) Sulfate
Phosphate-removing agents(not defined for Cefdinir): Lanthanum Carbonate Hydrate,
Ferric citrate, Calcium Carbonate
selectivity with P-glycoprotein, a typical efflux transporter. In general, inhibition of CYP potentiates both pharmacological and adverse actions of a
drug, and induction of CYP reduces them. However, when metabolite(s) are pharmacologically active, the situation may be reversed. Usually, degree
of DDI is more evident when victim drugs are given orally compared with other route of administration.
SSRIs: Fluvoxamine
Quinolones: Ciprofloxacin, Enoxacin, Clinafloxacin
NSAIDs: Rofecoxib
Contraceptives: (progesterone and ethinylestradiol)
Antiarrhythmics: Mexiletine
Vitiligo therapeutic agents: Methoxsalen
Muscle relaxant: Idrocilamide
Anticonvulsants: Phenytoin
Others: smoking
Induction of CYP2B6
intermediate 21%
extensive 79%
DNRIs: Bupropion
16)
Antiretrovirals: Efavirenz(EFV)
Inhibition of CYP2C8
extensive 100%
★Antidiabetic agents: Repaglinide, Pioglitazone
★Antineoplastic agents(oral drug): Bexarotene
Leukotriene-receptor antagonists: Montelukast
Antilipemic agents: Gemfibrozil※
Iron chelating agents: Deferasirox
Immunosuppressive agents: Cyclosporin
Antituberculosis agents: Rifampicin
Inhibition and induction of
CYP2C9
intermediate 4%
extensive 96%
★Anticoagulants: Warfarin
★Antidiabetic agents: Glimepiride, Tolbutamide, Glibenclamide, Nateglinide
★Anticonvulsants: Phenytoin
N SAIDs: Diclofenac, Celecoxib, Ibuprofen
Antilipemic agents: Fluvastatin
Fluorinated pyrimidine antagonist 2): TS-1※, UFT※, Tegafur※, Fluorouracil※,
Doxifluridine※, Capecitabine※, Carmofur※
Azoles: Miconazole, Fluconazole
Sulfonamides: Sulfaphenazole
Antiarrhythmics: Amiodarone
Antigout agents: Bucolome
Immunosuppressive agents: Cyclosporin
Antituberculosis agents: Rifampicin
Antineoplastic agents(oral drug): Enzalutamide
Anticonvulsants: Phenobarbital, Carbamazepine
Antiemetics: Aprepitant
Inhibition and induction of
CYP2C19
poor 16%
intermediate 48%
extensive 36%
★A zoles: Voriconazole
Proton-pump inhibitors: Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole
★Antiepileptic agents: Clobazam, S-Mephenytoin
Benzodiazepines: Diazepam, Etizolam
3)
Platelet-aggregation inhibitors: Clopidogrel
S SRIs: Sertraline, Escitalopram
SSRIs: Fluvoxamine, Fluoxetine
Platelet-aggregation inhibitors: Ticlopidine※
Azoles: Voriconazole, Fluconazole
Diuretics: Tienilic acid
Antidepressants: Moclobemide
Antituberculosis agents: Rifampicin
Antiretrovirals: Ritonavir(RTV)
Antineoplastic agents(oral drug): Enzalutamide
Inhibition of CYP2D6
poor 3%
*10/*10 14%4)
intermediate 35%
extensive 48%
Gaucher's disease agents: Eliglustat
Antitussives: Dextromethorphan
5)
Genitourinary smooth muscle relaxants: Tolterodine
3)
Opiate agonists: Tramadol
SNRIs: Atomoxetine
★Antiarrhythmics: Encainide, Propafenone, Flecainide
3)
★Antineoplastic agents(oral drug): Tamoxifen
A ntidepressants: Trimipramine, Desipramine, Nortriptyline, Maprotiline, Venlafaxine,
Inhibition and induction of
CYP3A7)
intermediate 2%
extensive 98%
16)
Antiretrovirals: Efavirenz(EFV)
17)
★Benzodiazepines: Triazolam, Midazolam, Alprazolam, Brotizolam
★Insomnia agents: Suvorexant
★Immunosuppressive agents: Everolimus, Sirolimus, Tacrolimus
Antilipemic agents: Simvastatin, Lovastatin, Atorvastatin
Calcium-channel blocking agents: Nisoldipine, Felodipine, Azelnidipine, Nifedipine
Antipsychotics: Blonanserin, Quetiapine, Lurasidone
★Antipsychotics(Risk of LQTS): Pimozide
PDE-5 inhibitors: Vardenafil, Sildenafil, Tadalafil
Endothelin- receptor antagonists: Macitentan
Antidepressants: Buspirone
★Antineoplastic agents(oral drug): Bosutinib, Dasatinib, Crizotinib, Lapatinib, Ceritinib
★Antiretrovirals: Maraviroc(MVC), Darunavir(DRV), Indinavir(IDV), Lopinavir(LPV),
Saquinavir(SQV), Tipranavir(TPV), Rilpivirine(RPV)
★Anticoagulants: Rivaroxaban
Platelet-aggregation inhibitors: Ticagrelor
★Antiarrhythmics: Dronedarone
Vasopressin V2 receptor antagonists: Conivaptan, Tolvaptan
Mineralocorticoid receptor antagonists: Eplerenone
Selective serotonin agonists: Eletriptan
Corticosteroids(inhaled drug): Budesonide, Fluticasone
Antiemetics: Aprepitant
Opiate agonists: Alfentanil
8)
Antigout agents: Colchicine
Genitourinary smooth muscle relaxants: Darifenacin
SSRIs: Paroxetine※, Fluoxetine, Escitalopram
Allylamine antifungal agents: Terbinafine
Antiarrhythmics: Quinidine
Calcium receptor agonists: Cinacalcet
Genitourinary smooth muscle relaxants: Mirabegron 6)
SNRIs: Duloxetine
DNRIs: Bupropion
NSAIDs: Celecoxib
Antineoplastic agents: Dacomitinib
Antidepressants: Moclobemide
Azoles: Itraconazole, Voriconazole, Ketoconazole, Posaconazole,
Miconazole, Fluconazole
Antiretrovirals: Ritonavir(RTV) ※, Indinavir(IDV) ※, Cobicistat,
Nelfinavir(NFV) ※, Saquinavir(SQV) ※, Atazanavir(ATV) ※,
Fosamprenavir(FPV), Amprenavir(APV)
HCV protease inhibitors: Telaprevir, Boceprevir
Macrolides: Troleandomycin※, Clarithromycin※, Erythromycin※
Calcium-channel blocking agents: Diltiazem※, Verapamil※
Antidepressants: Nefazodone※
Fruit juice: Grapefruit juice※
Antineoplastic agents: Imatinib※, Crizotinib
Antiemetics: Aprepitant, Casopitant
Quinolones: Ciprofloxacin
Immunosuppressive agents: Cyclosporin
Benzodiazepines: Tofisopam
Vasopressin V2 receptor antagonists: Conivaptan
Antiarrhythmics: Dronedarone
Adenosine A 2A receptor antagonists: Istradefylline
9)
of unchanged drug may not be influenced by alternation in conjugation metabolism. In this situation, levels of metabolite would be altered due to DDI
associated with conjugation reaction.
Inhibition or induction of
glucuronide conjugation enzyme
Representative molecular species of
UGT are shown in {}. However, multiple
species are frequently involved in the
same reaction and the specification is
not conclusive.
★Anticonvulsants: Valproate{2B7} , Lamotrigine{1A4}
★Antiretrovirals: Zidovudine(AZT){2B7}
★Benzodiazepines: Lorazepam{1A3, 2B15}
★Immunosuppressive agents: Mycophenolate mofetil{1A9}
10)
★Antineoplastic agents(injection drug): Irinotecan{1A1}
N SAIDs: Indomethacin{2B7}, Ketoprofen{1A, 2B}, Naproxen{1A3}
Contraceptives: Ethinylestradiol{1A1}
Iron chelating agents: Deferasirox{1A1, 1A3}
Inhibition or induction
of MDR1 (P-glycoprotein) 7) involved
in restriction of intestinal
absorption and brain penetration
intermediate
(C3435T homozygotes)11): 18%
P−glycoprotein (P-gp) is expressed at the luminal membrane of enterocytes in the intestine and suppress absorption of drugs.
In addition, P-gp is expressed at the bile canalicular membrane in the liver and at the tubular luminal membrane in the kidney
and mediates biliary and renal excretion of drugs. Inhibition of P-gp promotes intestinal absorption and delays in excretion,
Inhibition of BCRP involved
in restriction of intestinal
absorption
reduced function
(C421A homozygotes): 12%
BCRP is expressed at the luminal membrane of enterocytes in the intestine and suppresses absorption of drugs. In addition,
BCRP is expressed at the bile canalicular membrane in the liver and at the tubular luminal membrane in the kidney and
mediates biliary and renal excretion of drugs. Inhibition of BCRP promotes intestinal absorption and delays in excretion, in
Inhibition of OATPs12) involved
in intestinal absorption
reduced function
(OATP2B1 C1457T homozygotes)
: 13%
OATPs are expressed at the luminal membrane of enterocytes in the intestines and mediate absorption of drugs into the blood.
Therefore, inhibition of OATPs may reduce blood drug concentration and pharmacological actions of substrate drugs.
Inhibition and induction
of OATP1B1 and/or OATP1B3
involved in uptake into the liver
increased function
(OATP1B1 A388G homozygotes)11): 40%
reduced function
(OATP1B1 T521C homozygotes): 3%
OATP1B1 and OATP1B3 are expressed at the basolateral membrane in hepatocytes and mediate hepatic uptake of drugs.
Inhibition of OATP1B1/1B3 may increase blood concentrations and pharmacological/adverse actions of substrate drugs.
Inhibition of OAT1
and/or OAT3 involved
in uptake into the kidney
Inhibition of MATEs
involved
in efflux from the kidney
★Antiretrovirals: Saquinavir(SQV), Indinavir(IDV)
★Antineoplastic agents(injection drug): Paclitaxel, Docetaxel
★Cardiac glycosides: Digoxin
★Immunosuppressive agents: Cyclosporin, Tacrolimus
★Anticoagulants: Dabigatran Etexilate, Edoxaban, Rivaroxaban
Renin inhibitors: Aliskiren
Antidiarrhea agents: Loperamide
β-adrenergic blocking agents: Celiprolol, Talinolol
Antihistamines: Fexofenadine
Calcium-channel blocking agents: Verapamil
★Antineoplastic agents: Diflomotecan, Nogitecan(Topotecan)
★Antineoplastic agents / antirheumatic agents: Methotrexate
Sulfonamides: Salazosulfapyridine
Antilipemic agents: Rosuvastatin
Antineoplastic agents(oral drug): Sunitinib
Antigout agents: Probenecid{1A}
Azoles: Fluconazole{2B7}
Antiretrovirals: Atazanavir(ATV){1A1}
Anticonvulsants: Valproate{1A1}
Antineoplastic agents(oral drug): Sorafenib{1A1}
Ezetimibe, Fluvastatin, Cerivastatin
H CV protease inhibitors: Asunaprevir, Vaniprevir, Simeprevir, Paritaprevir
Angiotensin receptor antagonists: Fimasartan, Valsartan, Olmesartan, Telmisartan
Endothelin-receptor antagonists: Bosentan, Ambrisentan, Atrasentan
★Antidiabetic agents: Glibenclamide, Repaglinide, Nateglinide
Antihistamines: Fexofenadine
★Antineoplastic agents(injection drug): Paclitaxel, Docetaxel
Angiotensin-converting enzyme inhibitors: Temocapril, Enalapril
Duretics: Torasemide
★Antiretrovirals: Lopinavir(LPV)
Carbapenems9): Panipenem, Meropenem, Imipenem
Antituberculosis agents: Rifampicin
Antiretrovirals: Ritonavir(RTV)
Contraceptives: Ethinylestradiol
Anticonvulsants: Phenobarbital, Phenytoin, Carbamazepine
in general and thus leads to an increase in pharmacological and adverse actions with increased blood drug concentration.
P-gp is also expressed in the brain and protects the brain against exposure of xenobiotics, thus inhibition of P-gp may increase
invasion of drugs into the brain.
Antiretrovirals: Ritonavir(RTV), Nelfinavir(NFV)
Azoles: Itraconazole, Ketoconazole
Macrolides: Erythromycin, Clarithromycin
Immunosuppressive agents: Cyclosporin
Antiarrhythmics: Quinidine
Calcium-channel blocking agents: Verapamil
Ketolides: Telithromycin
Antilipemic agents: Lovastatin
Vasopressin V2 receptor antagonists: Tolvaptan
SSRI: Fluvoxamine
Antineoplastic agents(oral drug): Lapatinib
Antituberculosis agents: Rifampicin
Others: St.John's wort
Anticonvulsants: Carbamazepine
general and thus leads to an increase in pharmacological and adverse actions with increased blood drug concentration. BCRP
is also expressed in the brain and in the mammary gland.
Hematopoietic agents: Eltrombopag
Others: Curcumin
β-adrenergic blocking agents: Celiprolol, Talinolol, Atenolol, Acebutolol
Antihistamines: Fexofenadine
Renin inhibitors: Aliskiren
★Antineoplastic agents: Etoposide
Leukotriene-receptor antagonists: Montelukast
A ntilipemic agents: Pravastatin, Atorvastatin, Rosuvastatin, Simvastatin, Pitavastatin,
Antituberculosis agents: Rifampicin, Rifabutin
Antineoplastic agents(oral drug): Enzalutamide
Anticonvulsants: Phenobarbital, Phenytoin, Carbamazepine
Antiretrovirals: Etravirine(ETR), Efavirenz(EFV)
Others: St.John's wort
Psychostimulants: Modafinil
Endothelin-receptor antagonists: Bosentan
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
star(★) indicate that more noticeable clinical risks would be arisen for these drugs compared with those without a star.
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
which are expressed in the intestine and liver predominantly. In general, inhibition of conjugation potentiates both the pharmacological and adverse
actions of a drug, and induction of conjugation reduces them. However, since conjugation takes place often after phase-1 oxidative metabolism, level
※
1)
c
Skeletal muscle relaxants: Tizanidine
Melatonin receptor agonists: Ramelteon, Melatonin
★Xanthine derivatives: Caffeine, Theophylline
SNRIs: Duloxetine
Antifibrotic agents: Pirfenidone
Nonergot-derivative dopamine receptor agonists: Ropinirole
Atypical antipsychotics: Clozapine, Olanzapine
5 -HT3 inhibitors: Alosetron, Ramosetron
Acetylcholinesterase inhibitors: Tacrine
Doxepin, Amitriptyline, Imipramine, Clomipramine
Transporter
Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba
University
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo
Graduate School of Pharmaceutical Sciences, The University of Tokyo
d
Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN
b
Inhibition and induction of
CYP1A2
intermediate 1%
extensive 99%
β-adrenergic blocking agents: Metoprolol, Nebivolol, Timolol, Propranolol
Antipsychotics: Perphenazine
5 -HT3 inhibitors: Tropisetron
Conjugation
a
Is DDI avoidable by adjusting timing of dose?
DDIs of proton-pump inhibitors are unavoidable due to their durative
pharmacological action. For other drugs, longer interval between the
doses is better in order to reduce significance of DDI.
In human, 57 genes of cytochrome P450 (CYP) are recognized. Among them, 23 species are belong to CYP1−3 families which are significantly
involved in drug metabolism. CYP3A4 is the most important drug metabolizing enzyme and mediates metabolism of approximately half of drugs in
the market. CYP3A4 is expressed in the liver and intestine, and other CYPs are expressed predominantly in the liver. CYP3A4 often shares substrate
Cytochrome
P450 (CYP)
Akihiro Hisakaa, Yoshiyuki Ohnob, Hiroshi Suzukib, Kazuya Maedac, Yuichi Sugiyamad
Fruit juice: Grapefruit juice, Orange juice, Apple juice
Immunosuppressive agents: Cyclosporin
Antituberculosis agents: Rifampicin(single-dose administration) 13)
HCV protease inhibitors: Telaprevir, Simeprevir, Asunaprevir, Vaniprevir,
Paritaprevir
Antilipemic agents: Gemfibrozil
Macrolides: Clarithromycin
Antiretrovirals: Atazanavir(ATV), Lopinavir(LPV), Darunavir(DRV),
Tipranavir(TPV)
Others: Quercetin
Antituberculosis agents: Rifampicin(repeated-dose administration) 13)
Antiretrovirals: Efavirenz(EFV)
OAT1 and OAT3 are expressed at the tubular basolateral membrane in the kidney and mediate renal excretion of drugs.
Inhibition of OATs may increase blood concentrations and pharmacological/adverse actions of substrate drugs.
★Antineoplastic agents / antirheumatic agents: Methotrexate
★Antiretrovirals: Zidovudine(AZT)
★Nucleoside and nucleotide analogs: Adefovir, Ganciclovir, Cidofovir
N SAIDs: Ketorolac, Indomethacin, Ketoprofen, Naproxen, Tenoxicam
Penicillins, Cephalosporins
Quinolones: Levofloxacin, Ofloxacin, Ciprofloxacin
Diuretics: Furosemide
14)
Neuraminidase inhibitors: Oseltamivir
★Antidiabetic agents: Sitagliptin
Angiotensin-converting enzyme inhibitors: Enalapril, Captopril
Histamine H2-antagonists: Famotidine
Antigout agents: Probenecid
NSAIDs: Indomethacin, Salicylic acid, Phenylbutazone
Antilipemic agents: Gemfibrozil
MATEs are expressed at the tubular luminal membrane in the kidney and mediate renal excretion of drugs.
Inhibition of MATEs may increase blood concentrations and pharmacological/adverse actions of substrate drugs. MATEs are also expressed in the liver.
Histamine H2-antagonists: Cimetidine
★Antidiabetic agents: Metformin
★Antiarrhythmics: Procainamide, Pilsicainide, Dofetilide
Diuretics: Triamterene
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.
Frequency of genetic variants described in this table, are estimated in Japanese population (poor: activity is deficient, intermediate: activity is approximately half of
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
and intermediate metabolizers even in the absence of DDI. DDI in poor and intermediate metabolizers is complex and unknown so far.
2) It has been reported that fluorouracils do not inhibit CYP2C9 directly in vitro, but decrease expression of CYP2C in vivo.
3) Drugs are pharmacologically activated by metabolism. Therefore, co-administration with inhibitors can cause decrease in pharmacological/adverse actions, and co-administration
of inducers is vice versa.
4) Activity of CYP2D6 is usually reduced to approximately 1/5 of extensive metabolizer in *10 homozygotes.
5) Clinical significance of associated DDIs is controversial, since metabolite(s) of tolterodine is also pharmacologically active.
6) Observed with double dose comparing usual dosage.
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
inhibitors of CYP3A4 and P-gp are separately shown in this table.
8) The degree of drug interaction would be increased when renal function is impaired.
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.
No report suggests DDI between carbapenems and other substrates of UGT.
10) Irinotecan is transformed to the pharmacologically active SN-38 by carboxyesterase and simultaneously to an inactive metabolite by CYP3A4. Therefore, inhibition of CYP3A4
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,
therefore, may cause adverse events such as neutropenia.
Histamine H2-antagonists: Cimetidine
Antiretrovirals: Dolutegravir15)
Diamino-pyrimidines: Trimethoprim
Antimalarial agents: Pyrimethamine
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
to be interpreted cautiously.
12) Target transporters are yet unknown.Some literatures suggest involvement of OATP1A2 and OATP2B1. Recent reports demonstrated that genetic polymorphisms of OATP2B1
affected the pharmacokinetics of some drugs.
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
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
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.
14) Blood concentration of an active metabolite of oseltamivir is increased due to the decrease in renal clearance when probenecid is co-administered.
15) OCT2 can also be inhibited at the clinical dose.
16) Listed based on an in vivo induction study and the observed effect might be partly attributable to induction of other pathway(s).
17) Before initiation of treatment with this medicine, patients should be genotyped for CYP2D6 to determine the CYP2D6 metaboliser status.
References:
1. Hisaka A, et al. Pharmacol. Ther. 2010; 125: 230-48.
2. Hisaka A, et al. Clin Pharmacokinet, 2009: 48: 653-66.
3. Maeda K, et al. Web-based database as a tool to examine drug-drug interactions involving transporters in: "Enzyme- and transporter-based drug-drug interactions" ed. by Pang KS,
Rodrigues AD, and Peter RM, Springer, New York, pp. 387-414 (2010).
4. Shitara Y, et al. Annu Rev Pharmacol Toxicol,2005: 45: 689-723.
PharmaTribune Vol.8 No.2 Suppl.1 (In press, 2016, original text in Japanese) Copyright 2016 Yuichi Sugiyama, et. al.
Published by Medical Tribune, Inc., 2-1-30, Kudan Minami, Chiyoda-ku Tokyo 102-0074, Japan All rights reserved.
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