Pharmacokinetics, Biodistribution and Toxicity Studies for Nanocarrier of Antitubercular Agent- Rifabutin

Abstract

Introduction: Rifabutin (RFB) is a lipophilic, semi-synthetic antibiotic given for the treatment of atypical mycobacterial infections along with drug susceptible tuberculosis infections. The major challenges in its usage include low oral bioavailability (~20%) mainly due to its low solubility and extensive first pass metabolism. Aim: The present study aims to explore the pharmacokinetics, biodistribution and toxicity of nanocarrier of RFB. Materials and Methods: An experimental animal study was carried out in Institute for Industrial Research and Toxicology, Ghaziabad, Uttar Pradesh, India. RFB nanocarriers were formulated by using solvent diffusion evaporation method with minor modifications and characterised for its physicochemical properties by using various techniques like Field Emission Scanning Electron Microscopy (FESEM), Dynamic Light Scattering (DLS) method, High-Performance Liquid Chromatography (HPLC), X-ray Diffractometry (XRD), in-vitro release study etc. Further nanocarriers were also studied for in-vivo analysis using pharmacokinetics, biodistribution and toxicity studies. GraphPad Prism Software (Version 5.02) was used for the statistical analysis. Results: Nanocarriers of RFB were developed and evaluated for its safety and efficacy. The results of evaluation of nanocarrier for physical and chemical attributes revealed that its particle size obtained was 305-325 nm with low Poly Dispersity Index (PDI) of 0.26-0.36 and the high drug encapsulation efficiency (62.45- 70.15%). The nanocarrier formulation showed a sustained release pattern in Simulated Intestinal Fluid (SIF) upto 48 hours and in Physiological Buffer System (PBS) upto 7 days. The invivo study showed that the nano-lipoidal drug has significant higher Tmax and Cmax plasma value with higher t1/2(h) values in comparison to plain drug. Moreover, the slow elimination rate (Kel) resulted in significant (p<0.001) prolonged half-life (t1/2), which was many fold higher than the plain drug. No significant change was observed in haematological and liver enzyme profile of rats in plain drug and drug with nano-lipoidal carrier. Nanocarriers showed that there was an increase cell survival rate in MTT assay as compared to normal drug. Conclusion: By using nanotechnology based formulations, dose and dosing frequency of drug administration can be reduced. Thus, RFB drug can be administered in more efficacious manner reducing its toxic side effects, which ultimately improves patient compliance.

Keywords

• bioavailability
• mycobacterium tuberculosis
• sustained release pattern