title: Investigation of the functional role of P-glycoprotein in limiting the oral bioavailability of lumefantrine.
abstract: In the quest to explore the reason for the low and variable bioavailability of lumefantrine, we investigated the possible role of P-glycoprotein (P-gp) in lumefantrine intestinal absorption. An in situ single-pass intestinal perfusion study in rats with the P-gp inhibitor verapamil or quinidine and an ATPase assay with human P-gp membranes indicated that lumefantrine is a substrate of P-gp which limits its intestinal absorption. To confirm these findings, an in vivo pharmacokinetic study was performed in rats. The oral administration of verapamil (10 mg/kg of body weight) along with lumefantrine caused a significant increase in its bioavailability with a concomitant decrease in clearance. The increase in bioavailability of lumefantrine could be due to inhibition of P-gp and/or cytochrome P450 3A in the intestine/liver by verapamil. However, in a rat intestinal microsomal stability study, lumefantrine was found to be resistant to oxidative metabolism. Further, an in situ permeation study clearly showed a significant role of P-gp in limiting the oral absorption of lumefantrine. Thus, the increase in lumefantrine bioavailability with verapamil is attributed in part to the P-gp-inhibitory ability of verapamil. In conclusion, lumefantrine is a substrate of P-gp, and active efflux by P-gp across the intestine partly contributed to the low/variable bioavailability of lumefantrine.
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors.lastname: Wahajuddin
authors.forename: Kanumuri S R
authors.initials: KS
authors.lastname: Raju
authors.forename: Sheelendra P
authors.initials: SP
authors.lastname: Singh
authors.forename: Isha
authors.initials: I
authors.lastname: Taneja
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D000078102:Lumefantrine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine