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.

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

“…42,43 Interestingly, in patients receiving NVP-based ART, the defective variant ABCB1 3435 TT genotype was significantly associated with high lumefantrine plasma concentration. Similarly, a previous study reported nonsignificant increase of lumefantrine clearance (13%) in carriers of homozygous wild type for CYP3A5*3.…”

Oil‐Fortified Maize Porridge Increases Absorption of Lumefantrine in Children with Uncomplicated Falciparum Malaria

“…The number of participants was sufficient to assess our PK objective, but insufficient for determining which patient variables could significantly explain the variability. Interpatient variability in LUM PK exposure may be partially attributed to differences in metabolism due to maturation (age) ; polymorphism of CYP3A4 enzymes ; metabolism or p‐glycoprotein efflux activity in intestinal epithelial cells ; physiological differences that may include food effect on gastric emptying and gastrointestinal (GIT) transit time. Other important factors such as pH of GIT contents may affect drug stability and solubility and hepatic blood flow .…”

A fast and sensitive method for quantifying lumefantrine and desbutyl-lumefantrine using LC–MS/MS

“…Patient related factors include gastrointestinal {GIT} physiological processes and food effect on absorption [132,135,137,138]. These include alterations in P H of GIT contents and hepatic blood flow [132]; drug efflux by ATP-binding cassette (ABC) transporters pglycoprotein and metabolism at the intestinal mucosa [139,140]. Gastric emptying varies with dietary content, mechanical effects such as volume and state of food, either solid or liquid and food viscosity [133,135,136].…”

“…Mechanisms responsible for poor LUM oral bioavailability are attributed to its physicochemical properties and GIT barriers to absorption [139]. The solubility of LUM and availability for absorption is enhanced by dietary fat [91,129,130].…”