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An<jats:italic>in situ<\/jats:italic>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<jats:italic>in vivo<\/jats:italic>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<jats:italic>in situ<\/jats:italic>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.<\/jats:p>","DOI":"10.1128\/aac.01382-13","type":"journal-article","created":{"date-parts":[[2013,11,5]],"date-time":"2013-11-05T04:07:25Z","timestamp":1383624445000},"page":"489-494","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":52,"title":["Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine"],"prefix":"10.1128","volume":"58","author":[{"family":"Wahajuddin","sequence":"first","affiliation":[{"name":"Pharmacokinetics and Metabolism Division, CSIR\u2014Central Drug Research Institute, Lucknow, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanumuri S. 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