title: Pharmacokinetics and tissue distribution studies of orally administered nanoparticles encapsulated ethionamide used as potential drug delivery system in management of multi-drug resistant tuberculosis.
abstract: Sustained release nanoformulations of second line anti-tubercular drugs can help in reducing their dosing frequency and improve patient's compliance in multi-drug resistant tuberculosis (MDR TB). The objective of the current study was to investigate the pharmacokinetics and tissues distribution of ethionamide encapsulated in poly (DL-lactide-co-glycolide) (PLGA) nanoparticles. The drug loaded nanoparticles were 286 ± 26 nm in size with narrow size distribution, and zeta-potential was -13 ± 2.5 mV. The drug encapsulation efficiency and loading capacity were 35.2 ± 3.1%w/w and 38.6 ± 2.3%w/w, respectively. Ethionamide-loaded nanoparticles were administered orally to mice at two different doses and the control group received free (unencapsulated) ethionamide. Ethionamide-loaded PLGA nanoparticles produced sustained release of ethionamide for 6 days in plasma against 6 h for free ethionamide. The Ethionamide was detected in organs (lung, liver, and spleen) for up to 5-7 days in the case of encapsulated ethionamide, whereas free ethionamide was cleared within 12 h. Ethionamide-loaded PLGA nanoparticles exhibited significant improvement in pharmacokinetic parameters, i.e. C(max), t(max), AUC₀₋∞, AUMC₀₋∞, and MRT of encapsulated ethionamide as compared with free ethionamide. Drug in nanoparticles also exhibited a dose proportional increase in the AUC₀₋∞ values. The pharmacodynamic parameters such as AUC₀₋₂₄/MIC, C(max)/MIC, and Time > MIC were also improved. PLGA nanoparticles of ethionamide have great potential in reducing dosing frequency of ethionamide in treatment of MDR TB.
authors.affiliation: Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.forename: Sadhna
authors.initials: S
authors.lastname: Sharma
authors.forename: Nusrat
authors.initials: N
authors.lastname: Shafiq
authors.forename: Promila
authors.initials: P
authors.lastname: Pandhi
authors.forename: Gopal Krishan
authors.initials: GK
authors.lastname: Khuller
authors.forename: Samir
authors.initials: S
authors.lastname: Malhotra
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D005000:Ethionamide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014018:Tissue Distribution; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D053769:Nanocapsules; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005000:Ethionamide