Transporter-Mediated Hepatic Uptake Plays an Important Role in the Pharmacokinetics and Drug-Drug Interactions of Montelukast

Clin Pharmacol Ther. 2017 Mar;101(3):406-415. doi: 10.1002/cpt.520. Epub 2016 Nov 18.


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.

MeSH terms

  • Acetates / pharmacokinetics
  • Acetates / pharmacology*
  • Animals
  • Clarithromycin / pharmacokinetics
  • Cytochrome P-450 CYP2C8 / drug effects*
  • Cytochrome P-450 CYP2C8 / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / metabolism
  • Dose-Response Relationship, Drug
  • Gemfibrozil / pharmacology
  • Haplorhini
  • Hepatocytes / metabolism
  • Liver / metabolism*
  • Liver-Specific Organic Anion Transporter 1 / antagonists & inhibitors
  • Models, Biological
  • Nucleic Acid Synthesis Inhibitors
  • Organic Anion Transporters / antagonists & inhibitors*
  • Organic Anion Transporters / metabolism
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology*
  • Rats
  • Rifampin / pharmacology


  • Acetates
  • Cytochrome P-450 CYP3A Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Nucleic Acid Synthesis Inhibitors
  • Organic Anion Transporters
  • Quinolines
  • Cytochrome P-450 CYP2C8
  • Clarithromycin
  • montelukast
  • Gemfibrozil
  • Rifampin