Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains.
Nanoparticles (NP) including liposomes are cleared by phagocytes of the mononuclear phagocyte system. High inter-patient variability in pharmacokinetics of PEGylated liposomal doxorubicin (PLD) has been reported. We hypothesized that genetic factors may be associated with the variable disposition of PLD. We evaluated plasma and tissue disposition of doxorubicin after administration of PLD at 6mg/kg IV ×1 via tail vein in 23 different male inbred mouse strains. An approximately 13-fold difference in plasma clearance of PLD was observed among inbred strains. We identified a correlation between strain-specific differences in PLD clearance and genetic variation within a genomic region encoding GULP1 (PTB domain containing engulfment adapter 1) protein using haplotype associated mapping and the efficient mixed-model association algorithms. Our results also show that Gulp1 expression in adipose tissue was associated with PLD disposition in plasma. Our findings suggest that genetic variants may be associated with inter-individual pharmacokinetic differences in NP clearance.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Gina
G
Song
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Oscar T
OT
Suzuki
The Animal Studies Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Charlene M
CM
Santos
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Andrew T
AT
Lucas
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Tim
T
Wiltshire
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: zamboni@email.unc.edu.
William C
WC
Zamboni
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004317:Doxorubicin; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D053758:Nanoparticles; D000071184:Pharmacogenomic Variants; D011092:Polyethylene Glycols
D048868:Adaptor Proteins, Signal Transducing; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin
Gulp1; Nanoparticles; PLD; Pharmacogenetics; Pharmacokinetics