title: Pharmacokinetics, biodistribution, and toxicity of folic acid-coated antiretroviral nanoformulations.
abstract: The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Puligujja
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Balkundi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Rhishikesh
authors.initials: R
authors.lastname: Thakare
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Fox
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: JoEllyn
authors.initials: J
authors.lastname: McMillan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA yalnouti@unmc.edu.
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate; D004334:Drug Administration Schedule; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism; D005526:Food, Formulated; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000737:chemistry; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics*; D020442:Poloxamer / Q000737:chemistry; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D004337:Drug Carriers; D009842:Oligopeptides; D011725:Pyridines; D020442:Poloxamer; D000069446:Atazanavir Sulfate; D005492:Folic Acid; D019438:Ritonavir