PMID- 27648490
OWN - NLM
STAT- MEDLINE
DCOM- 20170517
LR  - 20211204
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Linking)
VI  - 101
IP  - 3
DP  - 2017 Mar
TI  - Transporter-Mediated Hepatic Uptake Plays an Important Role in the 
      Pharmacokinetics and Drug-Drug Interactions of Montelukast.
PG  - 406-415
LID - 10.1002/cpt.520 [doi]
AB  - Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment 
      of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been 
      suggested as a probe substrate for investigating CYP2C8 activity in vivo. We 
      evaluated the quantitative role of hepatic uptake transport in its 
      pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized 
      with significant active uptake in human hepatocytes, and showed affinity towards 
      organic anion transporting polypeptides (OATPs) in transfected cell systems. 
      Single-dose rifampicin, an OATP inhibitor, decreased montelukast clearance in 
      rats and monkeys. Clinical DDIs of montelukast were evaluated using 
      physiologically based pharmacokinetic modeling; and simulation of the 
      interactions with gemfibrozil-CYP2C8 and OATP1B1/1B3 inhibitor, 
      clarithromycin-CYP3A and OATP1B1/1B3 inhibitor, and itraconazole-CYP3A inhibitor, 
      implicated OATPs-CYP2C8-CYP2C8 interplay as the primary determinant of 
      montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in 
      the pharmacokinetics of montelukast, which should be taken into account when 
      interpreting clinical interactions.
CI  - (c) 2016 American Society for Clinical Pharmacology and Therapeutics.
FAU - Varma, M V
AU  - Varma MV
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Kimoto, E
AU  - Kimoto E
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Scialis, R
AU  - Scialis R
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Bi, Y
AU  - Bi Y
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Lin, J
AU  - Lin J
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Eng, H
AU  - Eng H
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Kalgutkar, A S
AU  - Kalgutkar AS
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Cambridge, Massachusetts, 
      USA.
FAU - El-Kattan, A F
AU  - El-Kattan AF
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Cambridge, Massachusetts, 
      USA.
FAU - Rodrigues, A D
AU  - Rodrigues AD
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
FAU - Tremaine, L M
AU  - Tremaine LM
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
LA  - eng
PT  - Journal Article
DEP - 20161118
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (Acetates)
RN  - 0 (Cyclopropanes)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Liver-Specific Organic Anion Transporter 1)
RN  - 0 (Nucleic Acid Synthesis Inhibitors)
RN  - 0 (Organic Anion Transporters)
RN  - 0 (Quinolines)
RN  - 0 (Sulfides)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C8)
RN  - H1250JIK0A (Clarithromycin)
RN  - MHM278SD3E (montelukast)
RN  - Q8X02027X3 (Gemfibrozil)
RN  - VJT6J7R4TR (Rifampin)
SB  - IM
MH  - Acetates/pharmacokinetics/*pharmacology
MH  - Animals
MH  - Clarithromycin/pharmacokinetics
MH  - Cyclopropanes
MH  - Cytochrome P-450 CYP2C8/*drug effects/*metabolism
MH  - Cytochrome P-450 CYP3A Inhibitors/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Gemfibrozil/pharmacology
MH  - Haplorhini
MH  - Hepatocytes/metabolism
MH  - Liver/*metabolism
MH  - Liver-Specific Organic Anion Transporter 1/antagonists & inhibitors
MH  - Models, Biological
MH  - Nucleic Acid Synthesis Inhibitors
MH  - Organic Anion Transporters/*antagonists & inhibitors/metabolism
MH  - Quinolines/pharmacokinetics/*pharmacology
MH  - Rats
MH  - Rifampin/pharmacology
MH  - Sulfides
EDAT- 2016/09/21 06:00
MHDA- 2017/05/18 06:00
CRDT- 2016/09/21 06:00
PHST- 2016/07/06 00:00 [received]
PHST- 2016/08/25 00:00 [revised]
PHST- 2016/09/14 00:00 [accepted]
PHST- 2016/09/21 06:00 [pubmed]
PHST- 2017/05/18 06:00 [medline]
PHST- 2016/09/21 06:00 [entrez]
AID - 10.1002/cpt.520 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2017 Mar;101(3):406-415. doi: 10.1002/cpt.520. Epub 2016 Nov 
      18.