Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier

Quantitative comparison with other hepatotropic ligands

Ken Ichi Ogawara, Susumu Hasegawa, Makiya Nishikawa, Yoshinobu Takakura, Mitsuru Hashida

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

To assess the feasibility of mannosylated macromolecules as a liver-specific carrier system, hepatic uptake characteristics of mannosylated bovine serum albumin (Man-BSA) were pharmacokinetically investigated. After intravenous injection, 111In-Man18-BSA accumulated in the liver up to 70% of dose at 2 h; the endothelial cells and Kupffer cells contributed about 66% and 21% of the uptake, respectively. In single-pass perfusion experiments using rat liver at varying inflow concentrations (0.1-2.0 μg/ml), 111In-Man18-BSA and 111In-Man33-BSA were continuously extracted by the liver and their extraction ratios decreased with the increasing inflow concentrations. The outflow curves of each 111In-Man-BSA at three concentrations were simultaneously fitted to a pharmacokinetic model including a binding to the cell surface and an internalization, by using a nonlinear regression program MULTI(RUNGE). The binding constant augmented with the increase in the number of mannose per BSA, whereas the internalization rate constant was quite comparable for both derivatives. The pharmacokinetic analysis has demonstrated that the uptake process of 111In-Man-BSA is characterized to possess fewer binding sites and a greater internalization rate in comparison with other liver-specific carriers such as galactosylated, succinylated and cationized BSAs. These results will provide useful information in designing drug targeting systems to the liver nonparenchymal cells via mannose receptors.

Original languageEnglish
Pages (from-to)349-360
Number of pages12
JournalJournal of Drug Targeting
Volume6
Issue number5
Publication statusPublished - 1999

Fingerprint

Pharmacokinetics
Ligands
Liver
Kupffer Cells
Drug Delivery Systems
mannose-bovine serum albumin conjugate
Intravenous Injections
Endothelial Cells
Perfusion
Binding Sites

Keywords

  • Binding
  • Internalization
  • Liver perfusion
  • Mannose receptor
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier : Quantitative comparison with other hepatotropic ligands. / Ogawara, Ken Ichi; Hasegawa, Susumu; Nishikawa, Makiya; Takakura, Yoshinobu; Hashida, Mitsuru.

In: Journal of Drug Targeting, Vol. 6, No. 5, 1999, p. 349-360.

Research output: Contribution to journalArticle

Ogawara, Ken Ichi ; Hasegawa, Susumu ; Nishikawa, Makiya ; Takakura, Yoshinobu ; Hashida, Mitsuru. / Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier : Quantitative comparison with other hepatotropic ligands. In: Journal of Drug Targeting. 1999 ; Vol. 6, No. 5. pp. 349-360.
@article{a42c1eb06bd94bf5b77020b03089f0cb,
title = "Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier: Quantitative comparison with other hepatotropic ligands",
abstract = "To assess the feasibility of mannosylated macromolecules as a liver-specific carrier system, hepatic uptake characteristics of mannosylated bovine serum albumin (Man-BSA) were pharmacokinetically investigated. After intravenous injection, 111In-Man18-BSA accumulated in the liver up to 70{\%} of dose at 2 h; the endothelial cells and Kupffer cells contributed about 66{\%} and 21{\%} of the uptake, respectively. In single-pass perfusion experiments using rat liver at varying inflow concentrations (0.1-2.0 μg/ml), 111In-Man18-BSA and 111In-Man33-BSA were continuously extracted by the liver and their extraction ratios decreased with the increasing inflow concentrations. The outflow curves of each 111In-Man-BSA at three concentrations were simultaneously fitted to a pharmacokinetic model including a binding to the cell surface and an internalization, by using a nonlinear regression program MULTI(RUNGE). The binding constant augmented with the increase in the number of mannose per BSA, whereas the internalization rate constant was quite comparable for both derivatives. The pharmacokinetic analysis has demonstrated that the uptake process of 111In-Man-BSA is characterized to possess fewer binding sites and a greater internalization rate in comparison with other liver-specific carriers such as galactosylated, succinylated and cationized BSAs. These results will provide useful information in designing drug targeting systems to the liver nonparenchymal cells via mannose receptors.",
keywords = "Binding, Internalization, Liver perfusion, Mannose receptor, Pharmacokinetics",
author = "Ogawara, {Ken Ichi} and Susumu Hasegawa and Makiya Nishikawa and Yoshinobu Takakura and Mitsuru Hashida",
year = "1999",
language = "English",
volume = "6",
pages = "349--360",
journal = "Journal of Drug Targeting",
issn = "1061-186X",
publisher = "Informa Healthcare",
number = "5",

}

TY - JOUR

T1 - Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier

T2 - Quantitative comparison with other hepatotropic ligands

AU - Ogawara, Ken Ichi

AU - Hasegawa, Susumu

AU - Nishikawa, Makiya

AU - Takakura, Yoshinobu

AU - Hashida, Mitsuru

PY - 1999

Y1 - 1999

N2 - To assess the feasibility of mannosylated macromolecules as a liver-specific carrier system, hepatic uptake characteristics of mannosylated bovine serum albumin (Man-BSA) were pharmacokinetically investigated. After intravenous injection, 111In-Man18-BSA accumulated in the liver up to 70% of dose at 2 h; the endothelial cells and Kupffer cells contributed about 66% and 21% of the uptake, respectively. In single-pass perfusion experiments using rat liver at varying inflow concentrations (0.1-2.0 μg/ml), 111In-Man18-BSA and 111In-Man33-BSA were continuously extracted by the liver and their extraction ratios decreased with the increasing inflow concentrations. The outflow curves of each 111In-Man-BSA at three concentrations were simultaneously fitted to a pharmacokinetic model including a binding to the cell surface and an internalization, by using a nonlinear regression program MULTI(RUNGE). The binding constant augmented with the increase in the number of mannose per BSA, whereas the internalization rate constant was quite comparable for both derivatives. The pharmacokinetic analysis has demonstrated that the uptake process of 111In-Man-BSA is characterized to possess fewer binding sites and a greater internalization rate in comparison with other liver-specific carriers such as galactosylated, succinylated and cationized BSAs. These results will provide useful information in designing drug targeting systems to the liver nonparenchymal cells via mannose receptors.

AB - To assess the feasibility of mannosylated macromolecules as a liver-specific carrier system, hepatic uptake characteristics of mannosylated bovine serum albumin (Man-BSA) were pharmacokinetically investigated. After intravenous injection, 111In-Man18-BSA accumulated in the liver up to 70% of dose at 2 h; the endothelial cells and Kupffer cells contributed about 66% and 21% of the uptake, respectively. In single-pass perfusion experiments using rat liver at varying inflow concentrations (0.1-2.0 μg/ml), 111In-Man18-BSA and 111In-Man33-BSA were continuously extracted by the liver and their extraction ratios decreased with the increasing inflow concentrations. The outflow curves of each 111In-Man-BSA at three concentrations were simultaneously fitted to a pharmacokinetic model including a binding to the cell surface and an internalization, by using a nonlinear regression program MULTI(RUNGE). The binding constant augmented with the increase in the number of mannose per BSA, whereas the internalization rate constant was quite comparable for both derivatives. The pharmacokinetic analysis has demonstrated that the uptake process of 111In-Man-BSA is characterized to possess fewer binding sites and a greater internalization rate in comparison with other liver-specific carriers such as galactosylated, succinylated and cationized BSAs. These results will provide useful information in designing drug targeting systems to the liver nonparenchymal cells via mannose receptors.

KW - Binding

KW - Internalization

KW - Liver perfusion

KW - Mannose receptor

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=0032949254&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032949254&partnerID=8YFLogxK

M3 - Article

VL - 6

SP - 349

EP - 360

JO - Journal of Drug Targeting

JF - Journal of Drug Targeting

SN - 1061-186X

IS - 5

ER -