Gender differences in pharmacokinetics of lumefantrine and its metabolite desbutyl‐lumefantrine in rats

Wahajuddin,; Singh, Sheelendra Pratap; Jain, Girish Kumar

doi:10.1002/bdd.1786

Cited by 13 publications

(1 citation statement)

References 21 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The oral and i.v. doses of lumefantrine were selected on the basis of the sensitivity of the method and previous understanding about the pharmacokinetics of lumefantrine (9,23). The verapamil formulation (solution) was prepared by dissolving it in distilled water, while the lumefantrine formulation (suspension) was prepared in 0.25% sodium CMC.…”

Section: P-gp Atpase Assaymentioning

confidence: 99%

Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

Wahajuddin

Raju

Singh

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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.

show abstract

Section: P-gp Atpase Assaymentioning

confidence: 99%

Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

Wahajuddin

Raju

Singh

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

A Water‐Soluble Polymer‐Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria

Matshe

Tshweu

Mvango

et al. 2023

Macromolecular Bioscience

View full text Add to dashboard Cite

Uncomplicated malaria is effectively treated with oral artemisinin‐based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water‐soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two‐part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water‐soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl‐lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer‐lumefantrine shows potential for entering the clinic to meet the need for a one‐course combination treatment for severe malaria.

show abstract

Optimization and evaluation of lipid emulsions for intravenous co-delivery of artemether and lumefantrine in severe malaria treatment

Yang

Gao

Zhou

et al. 2018

Drug Deliv. and Transl. Res.

View full text Add to dashboard Cite

Parenteral therapy for severe and complicated malaria is necessary, but currently available parenteral antimalarials have their own drawbacks. As for recommended artemisinin-based combination therapy, antimalarial artemether and lumefantrine are limited in parenteral delivery due to their poor water solubility. Herein, the aim of this study was to develop the lipid-based emulsions for intravenous co-delivery of artemether and lumefantrine. The lipid emulsion was prepared by high-speed shear and high-pressure homogenization, and the formulations were optimized mainly by monitoring particle size distribution under autoclaved conditions. The final optimal formulation was with uniform particle size distribution (~ 220 nm), high encapsulation efficiency (~ 99%), good physiochemical stability, and acceptable hemolysis potential. The pharmacokinetic study in rats showed that C of artemether and lumefantrine for the optimized lipid emulsions were significantly increased than the injectable solution, which was critical for rapid antimalarial activity. Furthermore, the AUC of artemether and lumefantrine in the lipid emulsion group were 5.01- and 1.39-fold of those from the solution, respectively, suggesting enhanced bioavailability. With these findings, the developed lipid emulsion is a promising alternative parenteral therapy for the malaria treatment, especially for severe or complicated malaria.

show abstract

Gender differences in pharmacokinetics of lumefantrine and its metabolite desbutyl‐lumefantrine in rats

Cited by 13 publications

References 21 publications

Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

A Water‐Soluble Polymer‐Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria

Optimization and evaluation of lipid emulsions for intravenous co-delivery of artemether and lumefantrine in severe malaria treatment

Contact Info

Product

Resources

About