Pharmacokinetic Study on the Mechanism of Tissue Distribution of Doxorubicin: Interorgan and Interspecies Variation of Tissue-To-Plasma Partition Coefficients in Rats, Rabbits, and Guinea Pigs

Terasaki, Tetsuya; Iga, Tatsuji; Sugiyama, Yuichi; Hanano, Manabu

doi:10.1002/jps.2600731008

Cited by 71 publications

(32 citation statements)

References 23 publications

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“…The terminal half-life of DOX was similar in both groups (ϳ18 h). In control animals, 35% of the drug was unbound in plasma, which is consistent with previous studies (Terasaki et al, 1984). A significant 60% decrease in DOX plasma protein binding was seen in plasma from LPS-treated mice ( p Ͻ 0.001).…”

Section: Resultssupporting

confidence: 91%

“…Generally, although the initial distribution of DOX is rapid, extensive tissue accumulation occurs due to cell nuclei binding (Booth et al, 1998). Moreover, DOX distributes into erythrocytes with a typical blood/plasma concentration ratio of 2.4 (Terasaki et al, 1984). It is thus likely that the extent of tissue binding or partitioning into erythrocytes is altered in LPS- …”

Section: Altered Pharmacokinetics Of Dox In Endotoxin-treated Micementioning

confidence: 99%

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Impact of Endotoxin-Induced Changes in P-Glycoprotein Expression on Disposition of Doxorubicin in Mice

Hartmann

Vassileva²,

Piquette-Miller

2005

Drug Metab Dispos

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ABSTRACT:P-glycoprotein (PGP) encoded by the Mdr1 gene mediates the excretion of drugs in organs such as the liver and kidney. Inflammation has been shown to suppress the expression and activity of PGP in rodent liver, thus potentially altering the pharmacokinetics of drugs that are substrates of PGP. Here we examined the effect of endotoxin (lipopolysaccharide; LPS)-induced inflammation on the disposition of the PGP substrate doxorubicin (DOX) in the mouse. Male CD-1 mice received 5 mg/kg LPS intraperitoneally. DOX (5 mg/kg) was administered intravenously 24 h after LPS treatment. The time course of DOX levels in plasma, urine, bile, and tissues was analyzed by high performance liquid chromatography. PGP protein and mRNA expression in liver and kidney was measured using Western blots and reverse transcriptase polymerase chain reaction. As compared to controls, LPS-treated mice exhibited a significant decrease (50%) in biliary clearance and 3-fold increased renal clearance of DOX. These changes were associated with strongly reduced PGP protein levels (30% controls, p < 0.05) in the liver and increased PGP levels in the kidney (140% controls, p < 0.05). Hepatic mRNA levels of all Mdr isoforms were reduced in LPS-treated mice, whereas renal Mdr1b levels were increased. In LPS-treated mice, we also measured an increased area under the plasma concentration-time curve and reduced systemic clearance of DOX, as well as a 2-to 5-fold increase in the urinary excretion of the doxorubicin and doxorubicinol aglycones. Our data suggest that endotoxin-induced inflammation in mice causes differential regulation of PGP in liver and kidney, thereby altering the clearance profile of DOX.

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Section: Resultssupporting

confidence: 91%

Section: Altered Pharmacokinetics Of Dox In Endotoxin-treated Micementioning

confidence: 99%

Impact of Endotoxin-Induced Changes in P-Glycoprotein Expression on Disposition of Doxorubicin in Mice

Hartmann

Vassileva²,

Piquette-Miller

2005

Drug Metab Dispos

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“…Adsorption, insertion and flip-flop can be distinguished as consecutive stages in the transport of this compound across membranes (Regev and Eytan, 1997;Lecompte et al, 2002). Studies performed with model systems, such as large unilamellar vesicles, E. coli mutants and erythrocytes, revealed that membrane potential, pH and electrostatic forces play important roles in this (Terasaki et al, 1984;Nishiyama et al, 1992;de Wolf et al, 1993;Speelmans et al, 1997). Furthermore, hydrophobic interactions, membrane fluidity and drug lipophilicity are decisive for efficient drug import (Jedrzejczak et al, 1999;Schuldes et al, 2001).…”

mentioning

confidence: 99%

N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx

et al. 2004

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Anticancer drugs generally have intracellular targets, implicating transport over the plasma membrane. For amphiphilic agents, such as the anthracycline doxorubicin, this occurs by passive diffusion. We investigated whether exogenous membrane-permeable lipid analogues improve this drug influx. Combinations of drugs and lipid analogues were coadministered to cultured endothelial cells and various tumour cell lines, and subsequent drug accumulation in cells was quantified. We identified N-hexanoyl-sphingomyelin (SM) as a potent enhancer of drug uptake. Low micromolar amounts of this short-chain sphingolipid, being not toxic itself, enhanced the uptake of doxorubicin up to 300% and decreased its EC 50 toxicity values seven-to 14-fold. N-hexanoyl SM acts at the level of the plasma membrane, but was found not incorporated in (isolated) lipid rafts, and artificial disruption or elimination of raft constituents did not affect its drug uptake-enhancing effect. Further, any mechanistic role of the endocytic machinery, membrane leakage or ABCtransporter-mediated efflux could be excluded. Finally, a correlation was established between the degree of drug lipophilicity, as defined by partitioning in a two-phase octanol -water system, and the susceptibility of the drug towards the uptake-enhancing effect of the sphingolipid. A clear optimum was found for amphiphilic drugs, such as doxorubicin, epirubicin and topotecan, indicating that N-hexanoyl-SM might act by modulating the average degree of plasma membrane lipophilicity, in turn facilitating transbilayer drug diffusion. The concept of short-chain sphingolipids as amphiphilic drug potentiators provides novel opportunities for improving drug delivery technologies.

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“…Various determining factors have been identified for the tissue distribution of certain types of drugs. For example, binding to the nuclei is involved in the tissue distribution of doxorubicin (Terasaki et al, 1984). The K p values for vinca alkaloids, such as vincristine and vinblastine, correlate with the tissue tubulin concentration (Wierzda et al, 1987(Wierzda et al, , 1988.…”

mentioning

confidence: 99%

Mechanism for the Tissue Distribution of Grepafloxacin, a Fluoroquinolone Antibiotic, in Rats

Suzuki

Kato²,

Sasabe³

et al. 2002

Drug Metab Dispos

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ABSTRACT:This study was carried out to investigate the most important factor(s) governing the tissue distribution of grepafloxacin (GPFX), a fluoroquinolone antibiotic, in rats. The tissue-to-blood concentration ratio (K p ) of GPFX at steady state during constant infusion was highest in the lung, followed by the pancreas, kidney, and spleen. After bolus injection, GPFX was efficiently taken up by most of the organs examined, the uptake clearance other than the lung being almost blood flow-limited. Approximately 10% of the intravenously injected dose was rapidly trapped by the lung, but GPFX distribution rapidly decreased within 30 s due to the washout by the plasma flow. Thus, the higher distribution of GPFX to the lung compared with the other organs cannot be accounted for by a difference in its uptake or efflux. Subcellular fractionation after the infusion indicated that GPFX is primarily distributed to the organelle fractions in most organs, 60% of lung-associated GPFX being recovered in the nucleus and plasma membrane fraction. Such subcellular distribution in the lung was proportional to the phosphatidylserine (PhS) content of each fraction. The steadystate K p value in each tissue in vivo also correlated with the tissue content of PhS. GPFX preferentially binds to PhS, compared with other phospholipids, and this binding was inhibited by weakly basic drugs, such as quinidine, imipramine, and propranolol, that have also been reported to bind to PhS. The association of GPFX with PhS synthase transformants of Chinese hamster ovary (CHO-K1) cells depends on the PhS content of each cell line, this association being also inhibited by basic drugs. These results suggest that binding of GPFX to PhS is the major determinant of the high distribution of GPFX to the lung.

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Pharmacokinetic Study on the Mechanism of Tissue Distribution of Doxorubicin: Interorgan and Interspecies Variation of Tissue-To-Plasma Partition Coefficients in Rats, Rabbits, and Guinea Pigs

Cited by 71 publications

References 23 publications

Impact of Endotoxin-Induced Changes in P-Glycoprotein Expression on Disposition of Doxorubicin in Mice

Impact of Endotoxin-Induced Changes in P-Glycoprotein Expression on Disposition of Doxorubicin in Mice

N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx

Mechanism for the Tissue Distribution of Grepafloxacin, a Fluoroquinolone Antibiotic, in Rats

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