Pharmacokinetic analysis of in vivo disposition of succinylated proteins targeted to liver nonparenchymal cells via scavenger receptors: importance of molecular size and negative charge density for in vivo recognition by receptors.
In vivo disposition characteristics of succinylated (Suc-) proteins were studied after intravenous injection in mice in relation to their molecular characteristics as negatively charged macromolecules. Recombinant superoxide dismutase (SOD; molecular mass, 32 kDa), bovine serum albumin (BSA; molecular mass, 67 kDa), and bovine IgG (molecular mass, 150 kDa) were used to produce succinylated derivatives with different degrees of modification. (111)In-labeled Suc-SODs were rapidly excreted into the urine with no significant hepatic uptake. In contrast, (111)In-Suc-BSA and Suc-IgG were significantly taken up by liver nonparenchymal cells via scavenger receptors (SRs) according to the degree of succinylation and the dose injected. Interestingly, highly succinylated BSAs exhibited significant accumulation in the kidney at higher doses when the hepatic uptake was saturated. Pharmacokinetic analysis demonstrated that the hepatic uptake of succinylated proteins depended on the molecular size and the estimated surface density of succinylated amino residues. Further analysis based on a physiological pharmacokinetic model, involving a saturable process with Michaelis-Menten kinetics, revealed that the surface density of negative charges was correlated with the affinity of larger succinylated proteins for the hepatic SRs. Thus, the present study has provided useful basic information for a therapeutic strategy and the molecular design of succinylated proteins for use as drug carriers and therapeutic agents per se for SR-mediated targeting in vivo.
Yamasaki
Yasuomi
Y
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Sumimoto
Kazuya
K
Nishikawa
Makiya
M
Yamashita
Fumiyoshi
F
Yamaoka
Kiyoshi
K
Hashida
Mitsuru
M
Takakura
Yoshinobu
Y
D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive; D003198:Computer Simulation; D016503:Drug Delivery Systems; D007204:Indium; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008657:Metabolic Clearance Rate; D051379:Mice; D018613:Microscopy, Confocal; D011066:Poly C / Q000494:pharmacology; D011069:Poly I / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D012709:Serum Albumin / Q000493:pharmacokinetics*
D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D012709:Serum Albumin; C034877:succinylalbumin; D007204:Indium; D011069:Poly I; D011066:Poly C