Non-Michaelis–Menten Type Hepatic Uptake of Liposomes in the Rat

Harashima, Hideyoshi; Kume, Yoshihiro; Yamane, Chizu; Kojima, Hiroshi

doi:10.1111/j.2042-7158.1992.tb05504.x

Cited by 22 publications

(4 citation statements)

References 21 publications

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“…[24][25][26] Blood concentrations at the indicated times denoted as C(t), are expressed in terms ofzID (injected dose) per mL of blood radioactivity (z ID W mL) (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Analysis of the Tissue Distribution of Octaarginine Modified Liposomes in Mice

Mudhakir

Akita

Khalil

et al. 2005

Drug Metabolism and Pharmacokinetics

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We recently found that octaarginine modified liposomes (R8-Lip) can be efficiently internalized by cultured cells. The purpose of the present study was to quantitatively determine the effect of R8-density on the tissue distribution of R8-Lip in mice, using their clearance as an index. R8 was introduced in the form of stearylated R8 (STR-R8). The liposomes were composed of cholesterol and egg phosphatidylcholine and were labeled with [(3)H]cholesteryl hexadecyl ether. Various densities of R8 (3%, 10% and 30%) containing liposomes were prepared with a diameter of approximately 70-80 nm. The tissue distribution of R8-Lip was determined after their i.v. administration into mice and the effect of R8-density on tissue distribution was compared with uptake clearance, the calculated tissue distribution divided by the area under the blood concentration-time course. As results, R8-Lip were more rapidly eliminated from circulating blood and distributed to many tissues, especially liver depending on the R8-density. However, the tissue uptake clearance represented similar value to that of positively charge liposomes. Based on these results, we conclude that the R8-dependent increase in R8-Lip in various tissues tested indicates that positive charge, but not PTD function derived from R8 predominantly responsible for the enhancement of tissue distribution. Therefore, it is suggested that topology control of R8 is important to exhibit the PTD function.

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“…[24][25][26] Blood concentrations at the indicated times denoted as C(t), are expressed in terms ofzID (injected dose) per mL of blood radioactivity (z ID W mL) (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Analysis of the Tissue Distribution of Octaarginine Modified Liposomes in Mice

Mudhakir

Akita

Khalil

et al. 2005

Drug Metabolism and Pharmacokinetics

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“…The principal factors responsible for the lifetime in circulation of a liposomal particle are two: (a) the rate of liposomal metabolism: rigid vesicles are slowly processed by the RES cells, inducing a temporary impairment on general particle phagocitosis (Kao and Juliano, 1981;Harashima et al, 1992) and (b) the level of plasma protein adsorption on membranes. Plasma protein adsorption is proportional to the exposition of hydrophobic defects, and decreases with the inclusion of Chol (Abra and Hunt, 1981;Semple et al, 1996).…”

Section: Protein Binding Assaymentioning

confidence: 99%

Development and in vitro characterisation of a benznidazole liposomal formulation

Morilla

Benavidez

Lopez

et al. 2002

International Journal of Pharmaceutics

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The purpose of this study was to find a multilamellar liposomal formulation for the antichagasic drug Benznidazole (BNZ). Different lipid matrices and organic solvents for BNZ were tested in order to obtain the liposomes with the highest g BNZ/100 g total lipid (D /TL) ratio. The best lipid matrices resulted from hydrogenated phosphatidylcholine from soybean (HSPC): Cholesterol (Chol): distearoyl-phosphatidylglycerol (DSPG) (molar ratio 2:2:1) prepared with BNZ dissolved in DMSO. Drug loading of 2 g BNZ/100 g total lipids at a total lipid concentration of 20 Á/30 mM was obtained. Two in vitro assays on the HSPC:Chol:DSPG formulation to predict its in vivo behaviour were performed. In the first experiments, after 60 min at 1 Á/450-fold dilution in buffer at 37 8C, the amount of drug associated to liposomes was reduced from 2 to 0.25 g BNZ/100 g total lipids at a rate of 65% (drug lost) min(1 at the first minute followed by 0.4% (drug lost) min(1 during the next hour. When incubated in plasma at 37 8C, the HSPC:Chol:DSPG formulations bounded a high amount of plasma proteins: r 0/2400 mg plasma protein per mmol total lipid. #

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“…It is known that the amount of administered lipid affects the tissue distribution of liposomes 14,15) and that liposome uptake by the liver is saturable. [16][17][18] With the use of 30-40 µg/ml of CPT-11 (this level is expected to be a lipid uptake saturation level), the lipid concentration was 78-104 mM, whereas with 5 µg/ml of CPT-11 (this level is below the uptake saturation level, and there was no difference in cellular uptake between the Sol and S-Lip groups), the lipid concentration was 13 mM. The CPT-11 concentration in the tumors in vivo was below 5 µg/g tumor, and the lipid concentration was below 13 mM.…”

Section: B Amentioning

confidence: 99%

Effective Irinotecan (CPT‐11)‐containing Liposomes: Intraliposomal Conversion to the Active Metabolite SN‐38

Sadzuka

Hirotsu

Hirota

1999

Japanese Journal of Cancer Research

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Irinotecan hydrochloride (CPT-11) is a prodrug of SN-38, which is an active metabolite with antitumor activity and side toxicity. The activities of CPT-11 and SN-38 depend on the closed lactone ring form of SN-38. We have examined the tissue distributions of the closed and open forms of CPT-11 and SN-38 in Lewis lung carcinoma-bearing mice after the administration of liposomal CPT-11 (S-Lip) and polyethyleneglycol (PEG)-modified S-Lip (S-PEG). The plasma concentrations of closed CPT-11 and SN-38 were increased by liposomalization, and their blood circulation was prolonged by the PEG modification. The concentrations of closed CPT-11 and SN-38 in tumors were elevated by both the liposomalization and PEG modification. The closed/total ratio of SN-38 in the tumors of the S-PEG group was greater than that of the CPT-11 solution (Sol) group. Thus, SN-38 was thought to be generated in intact liposomes containing CPT-11. The bile concentration of closed SN-38, which is responsible for CPT-11-induced intestinal disorder, was decreased by liposomalization. In an in vitro experiment, the SN-38/CPT-11 ratio in the tumor cells of the S-Lip group was found to be higher than that of the Sol group, and the ratio of the closed form of SN-38 was increased by the liposomalization. Laser scanning confocal microscopy showed the generation of SN-38 in the liposomal membrane after the incubation of S-Lip with carboxylesterase. It is therefore considered that a part of CPT-11 is converted to SN-38 in the intact liposomes.

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Non-Michaelis–Menten Type Hepatic Uptake of Liposomes in the Rat

Cited by 22 publications

References 21 publications

Pharmacokinetic Analysis of the Tissue Distribution of Octaarginine Modified Liposomes in Mice

Pharmacokinetic Analysis of the Tissue Distribution of Octaarginine Modified Liposomes in Mice

Development and in vitro characterisation of a benznidazole liposomal formulation

Effective Irinotecan (CPT‐11)‐containing Liposomes: Intraliposomal Conversion to the Active Metabolite SN‐38

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