Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains

详细信息    查看全文

• 作者：Gina Song ; PharmD ; PhD^a ; Oscar T. Suzuki ; PhD^a ; Charlene M. Santos ; RLATG^b ; ^c ; Andrew T. Lucas ; PharmD^a ; Tim Wiltshire ; PhD^a ; ^e ; William C. Zamboni ; PharmD ; PhD^a ; ^c ; ^d ; ^e ; ^{zamboni@email.unc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Nanoparticles ; PLD ; Gulp1 ; Pharmacokinetics ; Pharmacogenetics
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：12
• 期：7
• 页码：2007-2017
• 全文大小：1579 K

文摘

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 6 mg/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.