Harnessing herb-drug interactions for enhanced oral delivery of anti-HIV and antimalarial drugs using colloidal formulations

Abstract

Problem: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and malaria infect and kill a large population globally. Most of the current clinically used anti-HIV and antimalarial drugs have low bioavailability, either due to poor solubility and permeability, rapid clearance from anatomical reservoirs and poor retention at their site of action (e.g. by the p-glycoprotein efflux system), and extreme first-pass metabolism (e.g. by the cytochrome P450 enzymes). Hence, new approaches such as the incorporation of plant-derived absorption enhancers (PDAEs) into dosage forms, and exploration of nanocarriers as novel dosage forms, are needed and may provide a viable means that could improve the bioavailability of both anti-HIV and antimalarial drugs. Methods and procedures: Luminescent-based assay systems were used to screen for the effective inhibitory concentrations of the selected PDAEs against both p-glycoprotein and cytochrome P450 in vitro. Thereafter, an everted gut sac model was utilized to further screen for the effective concentrations of PDAEs combinations. Liposomes loaded with efavirenz or mefloquine as well as placebos were prepared using a thin-lipid film hydration technique and characterized for their entrapment efficiency, particle size, zeta potential, in vitro drug release, and in vitro drug permeability. Liposomes were further investigated for their biocompatibility (safety) with liver using H-4-II-E liver cells in vitro. Finally, the everted gut sac model was used for the drug transport studies across an intestinal membrane ex vivo. Drug analyses were performed using UV/Vis spectrophotometer for the entrapment efficiency, in vitro drug release, and in vitro drug permeability studies while high-performance liquid chromatography (HPLC) was used for the ex vivo studies. Main findings: Quercetin and curcumin had the most significant (p < 0.05) inhibitory vii effects on both p-glycoprotein and cytochrome P450 at concentrations of 75 μM and 100 μM, respectively. Drug-loaded liposomes prepared using l-α-phospatidylcholine, dioleoyl (DOPC) and cholesterol (CHOL) (1:1 mol/mol) as well as liposomes made of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CHOL and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (4:6:26 mol/mol/mol) exhibited better results in terms of their entrapment efficiency, particle size, zeta potential, in vitro drug release and permeability. Furthermore, these liposomes were biocompatible (safe) with liver cells. However, drugs and/or liposomes were unable to permeate through the porcine intestinal tissue, possibly due to high protein binding capacities of efavirenz and mefloquine. Conclusions: The DOPC:CHOL liposomes and the DSPC:CHOL:DPPC liposomes could provide a useful nanoformulation platform, which could ensure sustained release of both anti-HIV and antimalaria drugs. However, these dosage forms need further investigation using in vivo studies that could rectify the effect of protein binding, which was not investigated in this study.