Pharmacokinetics and tissue distribution of amphotericin B following oral administration of three lipid-based formulations to rats

Abstract

The objective of this study was to assess the pharmacokinetics and tissue distribution of amphotericin B (AmB) in rats following oral administration of three lipid-based formulations (iCo-009, iCo-010 and iCo-011). The lipid-based formulations were administered to rats at a dose of 10 mg/kg and blood samples were withdrawn at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 h, after which the animals were sacrificed and the body organs were collected for AmB quantification using a validated HPLC method. Plasma pharmacokinetics parameters were determined using non-compartmental analysis. The disappearance of AmB from plasma was the slowest following the administration of iCo-010 with MRT of 63 h followed by iCo-009 then iCo-011 (36 and 27 h). The AUC(0-24h) of iCo-009 and iCo-010 was 1.5-2-fold higher than that of iCo-011. The kidney exposure was comparable between iCo-009 and iCo-010 and was higher than that of iCo-011. The lung exposure was the highest following iCo-010 administration as compared to that of iCo-009. The distribution of AmB from plasma to tissues resulted in a high accumulation of AmB overtime with slow back-distribution to plasma. The pharmacokinetics profiles varied among the three formulations, despite the similarity in lipid composition between iCo-010 and iCo-011 and the presence of Peceol® as a common component in the formulations. The administration of oral iCo-010 could lead to higher steady state concentrations in the tissues after multiple dosing, which could lead to enhanced eradication of tissue borne fungal and parasitic infections.

Chain length affects pancreatic lipase activity and the extent and pH–time profile of triglyceride lipolysis

“…Different proposed mechanisms by which lipidic formulations increase oral bioavailability include the following: (a) promoting drug solubilisation in the gastrointestinal tract, by providing lipidic components that increase the inherent solubilisation capacity of the intestinal fluids [5], (b) delaying gastric emptying and transit time [6], (c) increasing apparent drug permeability through inhibition of efflux transporters such as P-glycoprotein [7,8], (d) changing the membrane fluidity of enterocytes [9], and (e) reducing hepatic first-pass metabolism if lymphatic transport is involved [10].…”

Promising nanotherapy in treating leishmaniasis

“…Later, Paliwal et al (2009) and Caliph et al (2000) showed that triglycerides with long chain are better transported to lymphatic system than the medium chain ones. Furthermore, Ibrahim et al (2013) demonstrated the influence of the type and ratio of lipids in the pharmacokinetic of AMB after oral administration. This study showed that lipid-based formulation could point to higher steady state concentrations in the tissues after multiple doses, which can improve the destruction of leishmanial parasites.…”

Investigational drugs for visceral leishmaniasis

“…Histopathological analysis detected no gastrointestinal, liver or kidney toxicity following multiple dose oral administration of iCo-010 in BALB/c mice 56 . Multiple dosing of oral iCo-010 led to higher steady state concentrations in the tissues of rats , which could lead to enhanced eradication of tissue borne fungal and parasitic infections 57 .…”