title: Transporter-Mediated Hepatic Uptake Plays an Important Role in the Pharmacokinetics and Drug-Drug Interactions of Montelukast.
abstract: 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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Varma
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kimoto
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: R
authors.initials: R
authors.lastname: Scialis
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: H
authors.initials: H
authors.lastname: Eng
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: El-Kattan
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Rodrigues
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Tremaine
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D017291:Clarithromycin / Q000493:pharmacokinetics; D003521:Cyclopropanes; D065727:Cytochrome P-450 CYP2C8 / Q000187:drug effects* / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015248:Gemfibrozil / Q000494:pharmacology; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors; D008954:Models, Biological; D019384:Nucleic Acid Synthesis Inhibitors; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012293:Rifampin / Q000494:pharmacology; D013440:Sulfides
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D019384:Nucleic Acid Synthesis Inhibitors; D027361:Organic Anion Transporters; D011804:Quinolines; D013440:Sulfides; D065727:Cytochrome P-450 CYP2C8; D017291:Clarithromycin; C093875:montelukast; D015248:Gemfibrozil; D012293:Rifampin