title: Evaluation of perfused porcine skin as a model system to quantitate tissue distribution of fullerene nanoparticles.
abstract: Nanomaterials are increasingly playing a role in society for uses ranging from biomedicine to microelectronics, however pharmacokinetic studies, which will be necessary for human health risk assessments, are limited. Tissue distribution, one component of pharmacokinetics, can be assessed by quantifying arterial extraction of materials in an isolated perfused porcine skin flap (IPPSF). The objective of this study was to assess the IPPSF as a model system to quantitate the distribution of fullerene nanoparticles (nC(60)) from the vascular space into tissues. IPPSFs were perfused for 4h with 0.885 microg/mL nC(60) in media with immunoglobulin G present (IgG(+)) or absent (IgG(-)) followed by a 4h perfusion with media only during a washout phase. Arterial and venous concentrations of nC(60) were measured in the media by HPLC-UV/vis chromatography. Steady state differences in the arterial and venous nC(60) concentrations were compared to determine extraction from the vascular space of the IPPSF, and the venous nC(60) concentration versus time profiles were used to calculate compartmental pharmacokinetic parameters. The steady state differences in the arterial and venous concentrations in the IPPSF were small with extraction percentages (mean+/-sd) of 8.2+/-5.7% and 4.2+/-6.7% for IgG(+) and IgG(-) media, respectively, and were not significantly different between the types of media. The venous concentrations of nC(60) in both types of media were best fit with a 2 compartment model with terminal half lives (harmonic mean) of 17.5 and 28.0 min for IgG(+) and IgG(-) media, respectively. The apparent volumes of distribution at steady state were 0.12+/-0.047 and 0.10+/-0.034 L/kg, for IgG(+) and IgG(-) media, respectively. By 4 h following infusion of nC(60), the recovery of nC(60) in the venous effluent was 94+/-5.5% and 97+/-6.8% of the infused nC(60) for IgG(+) and IgG(-) media, respectively. Based on the apparent volume of distribution, the low extraction during the perfusion, and the high percentage recovery following the washout phase, there was limited distribution of nC(60) from the vascular space into the extracellular space and negligible intracellular uptake of nC(60) in this system.
authors.affiliation: Center for Chemical Toxicology Research and Pharmacokinetics, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, United States. teresa_leavens@ncsu.edu
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Leavens
authors.forename: Xin Rui
authors.initials: XR
authors.lastname: Xia
authors.forename: Hyun A
authors.initials: HA
authors.lastname: Lee
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Monteiro-Riviere
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism; D003102:Colloids; D005260:Female; D037741:Fullerenes / Q000493:pharmacokinetics*; D007074:Immunoglobulin G / Q000378:metabolism; D023421:Models, Animal; D053758:Nanoparticles / Q000648:ultrastructure; D012867:Skin / Q000378:metabolism*; D013552:Swine; D014018:Tissue Distribution; D014680:Veins / Q000378:metabolism
chemical_list: D003102:Colloids; D037741:Fullerenes; D007074:Immunoglobulin G