Showing papers by "Ayman El-Kattan published in 2017"
TL;DR: Hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions.
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.
44 citations
TL;DR: The scope and utility of the Extended Clearance Classification System (ECCS) is discussed as a tool to support the rational staging of transporter victim DDI studies, both in vitro and clinical, and as a framework to inform clinical decisions during drug development.
Abstract: Drug transporters are recognized widely for their role in clinical pharmacokinetics and drug–drug interactions (DDIs). This has provided impetus to the inclusion of transporter substrate and inhibition studies in recent regulatory guidances. Here we discuss the scope and utility of the Extended Clearance Classification System (ECCS) as a tool to support the rational staging of transporter victim DDI studies, both in vitro and clinical, and as a framework to inform clinical decisions during drug development.
31 citations
TL;DR: L ligand‐based modeling approaches that use information obtained from the structure and molecular properties of the ligands have been applied to associate the drug‐related properties and transporter‐mediated disposition with the role of membrane transporters.
18 citations