Drug Accumulation (drug + accumulation)

Distribution by Scientific Domains


Selected Abstracts


Decrease in Tumor Apparent Permeability-Surface Area Product to a MRI Macromolecular Contrast Medium Following Angiogenesis Inhibition with Correlations to Cytotoxic Drug Accumulation

MICROCIRCULATION, Issue 5 2004
HEIKE E. DALDRUP-LINK
ABSTRACT Background: New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (KPS) in tumors to a macromolecular contrast medium (MMCM), to follow changes in KPS induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin. Methods: Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)30) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate KPS. These estimates of KPS were correlated with cytotoxic drug accumulations in the tumors. Results: Anti-VEGF treatment reduced KPS to MMCM in tumor tissue from 0.013 mL h,1 cm,3 (n = 9) at baseline to 0.003 mL h,1 cm,3 (n = 9) 24 h later (p < .05). The KPS values correlated significantly (r2 = .78; p < .0001) with the tumor cisplatin accumulation. No correlation (r2 = .001; p = .89) was found between KPS and tumor accumulation of the substantially smaller 5-FU molecule. Conclusions: MMCM-enhanced MRI can be used to detect and estimate changes in KPS to this contrast agent following a single dose of anti-VEGF antibody. The decline in KPS induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration. [source]


Role of the plasma membrane leaflets in drug uptake and multidrug resistance

FEBS JOURNAL, Issue 5 2010
Hagar Katzir
The present study aimed to investigate the role played by the leaflets of the plasma membrane in the uptake of drugs into cells and in their extrusion by P-glycoprotein and multidrug resistance-associated protein 1. Drug accumulation was monitored by fluorescence resonance energy transfer from trimethylammonium-diphenyl-hexatriene (TMA-DPH) located at the outer leaflet to a rhodamine analog. Uptake of dye into cells whose mitochondria had been inactivated was displayed as two phases of TMA-DPH fluorescence quenching. The initial phase comprised a rapid drop in fluorescence that was neither affected by cooling the cells on ice, nor by activity of mitochondria or ABC transporters. This phase reflects the association of dye with the outer leaflet of the plasma membrane. The subsequent phase of TMA-DPH fluorescence quenching occurred in drug-sensitive cell lines with a half-life in the range 20,40 s. The second phase of fluorescence quenching was abolished by incubation of the cells on ice and was transiently inhibited in cells with active mitochondria. Thus, the second phase of fluorescence quenching reflects the accumulation of dye in the cytoplasmic leaflet of the plasma membrane, presumably as a result of flip-flop of dye across the plasma membrane and slow diffusion from the inner leaflet into the cells. Whereas activity of P-glycoprotein prevented the second phase of fluorescence quenching, the activity of multidrug resistance-associated protein 1 had no effect on this phase. Thus, P-glycoprotein appears to pump rhodamines from the cytoplasmic leaflet either to the outer leaflet or to the outer medium. [source]


Triton-X-100-modified polymer and microspheres for reversal of multidrug resistance

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2001
Zhi Liu
Triton X-100 is a non-ionic detergent capable of reversing multidrug resistance (MDR) due to its interaction with cell membranes. However, it interacts with cells in a non-specific way, causing cytotoxicity. This work aimed to develop polymeric chemosensitizers that possess the ability to reverse MDR and lower toxic side effects. When being delivered to tumours, the polymeric chemosensitizers may also have longer retention times in tumours than the free detergent. Triton-X-100-immobilized dextran microspheres (T-MS) and inulin (T-IN) were prepared and characterized. Their cytotoxicity against multidrug-resistant Chinese hamster ovary cells (CHRC5) was compared with that of free Triton X-100 solutions. The in-vitro effect of the products on 3H-vinblastine accumulation by CHRC5 cells was determined. Both T-MS and T-IN showed a marked decrease in the cytotoxicity, as compared with free Triton solutions at equivalent concentrations. Drug accumulation by CHRC5 cells was increased over two fold in the presence of T-MS or T-IN. These results suggest that polymeric drug carriers with MDR-reversing capability and lower cytotoxicity may be prepared by immobilization of chemosensitizers. [source]


Blood,brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edema

EPILEPSIA, Issue 4 2009
Nicola Marchi
Summary Purpose:, Increased blood,brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods:, In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results:, BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion:, After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. [source]


Inhibition of PI3K/Akt partially leads to the inhibition of PrPC -induced drug resistance in gastric cancer cells

FEBS JOURNAL, Issue 3 2009
Jie Liang
Cellular prion protein (PrPC), a glycosyl-phosphatidylinositol-anchored membrane protein with unclear physiological function, was previous found to be upregulated in adriamycin (ADR)-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Overexpression of PrPC in gastric cancer has certain effects on drug accumulation through upregulation of P-glycoprotein (P-gp), which is suggested to play an important role in determining the sensitivity of tumor cells to chemotherapy and is linked to activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway. In the present study, we further investigate the role of the PI3K/Akt pathway in PrPC -induced multidrug-resistance (MDR) in gastric cancer. Immunohistochemistry and confocal microscope detection suggest a positive correlation between PrPC and phosphorylated Akt (p-Akt) expression in gastric cancer. Using established stable PrPC transfectant cell lines, we demonstrated that the level of p-Akt was increased in PrPC -transfected cells. Inhibition of PrPC expression by RNA interference resulted in decreased p-Akt expression. Inhibition of the PI3K/Akt pathway by one of its specific inhibitors, LY294002, or by Akt small interfering RNA (siRNA) resulted in decreased multidrug resistance of SGC7901 cells, partly through downregulation of P-gp induced by PrPC. Taken together, our results suggest that PrPC -induced MDR in gastric cancer is associated with activation of the PI3K/Akt pathway. Inhibition of PI3K/Akt by LY2940002 or Akt siRNA leads to inhibition of PrPC -induced drug resistance and P-gp upregulation in gastric cancer cells, indicating a possible novel mechanism by which PrPC regulates gastric cancer cell survival. [source]


Understanding cisplatin resistance using cellular models

IUBMB LIFE, Issue 11 2007
Britta Stordal
Abstract Many mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF-CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7-fold with a treatment dose of 1.6 ,g/ml. Cisplatin resistance in these cells correlated with increases in the antioxidant glutathione, yet treatment with buthionine sulphoximine, an inhibitor of glutathione synthesis, had no effect on resistance, suggesting that the increase in glutathione was not directly involved in cisplatin resistance. Two models were developed from H69 SCLC cells, H69-CP and H69CIS200 using 100 ng/ml or 200 ng/ml cisplatin respectively. Both cell models were 2-4 fold resistant to cisplatin, and have decreased expression of p21 which may increase the cell's ability to progress through the cell cycle in the presence of DNA damage. Both the H69-CP and H69CIS200 cells showed no decrease in cellular cisplatin accumulation. However, the H69-CP cells have increased levels of cellular glutathione and are cross resistant to radiation whereas the H69CIS200 cells have neither of these changes. This suggests that increases in glutathione may contribute to cross-resistance to other drugs and radiation, but not directly to cisplatin resistance. There are multiple resistance mechanisms induced by cisplatin treatment, even in the same cell type. How then should cisplatin-resistant cancers be treated? Cisplatin-resistant cell lines are often more sensitive to another chemotherapeutic drug paclitaxel (H69CIS200), or are able to be sensitized to cisplatin with paclitaxel pre-treatment (H69-CP). The understanding of this sensitization by paclitaxel using cell models of cisplatin resistance will lead to improvements in the clinical treatment of cisplatin resistant tumours. IUBMB Life, 59: 696-699, 2007 [source]


Phycocyanin liposomes for topical anti-inflammatory activity: in-vitro in-vivo studies

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2009
Maria Manconia
Abstract Objectives The aim of this work was to investigate the anti-inflammatory activity of C-phycocyanin (C-PC) on skin inflammation after topical administration and the influence of liposomal delivery on its pharmacokinetic properties. Methods Liposomes of different size and structure were prepared with different techniques using soy phosphatidylcholine and cholesterol. Vesicular dispersions were characterised by transmission electron microscopy, optical and fluorescence microscopy for vesicle formation and morphology, dynamic laser light scattering for size distribution, and Zetasizer for zeta-potential. C-PC skin penetration and permeation experiments were performed in vitro using vertical diffusion Franz cells and human skin treated with either free or liposomal drug dispersed in a Carbopol gel. Key findings The protein was mainly localised in the stratum corneum, while no permeation of C-PC through the whole skin thickness was detected. Two percent C-PC-encapsulating liposomes showed the best drug accumulation in the stratum corneum and the whole skin, higher than that of the corresponding free 2% C-PC gel. Moreover, skin deposition of liposomal C-PC was dose dependent since skin accumulation values increased as the C-PC concentration in liposomes increased. The topical anti-inflammatory activity of samples was evaluated in vivo as inhibition of croton oil-induced or arachidonic acid-induced ear oedema in rats. Conclusions The results showed that C-PC can be successfully used as an anti-inflammatory drug and that liposomal encapsulation is effective in improving its anti-inflammatory activity. [source]


Formulation and evaluation of nimodipine-loaded lipid microspheres

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2006
Jia Yu
The purpose of this study was to develop an alternative, improved and better tolerated formulation and investigate the pharmacokinetic profile of the new formulation of nimodipine (NM) compared with nimodipine ethanol solutions. Lipid microspheres (LMs) prepared using lecithin and vegetable oils have attracted a lot of interest owing to their versatile properties, such as non-immunogenicity, being easily biodegradable and exhibiting high entrapment efficiency. NM incorporated in LMs could reduce irritation by avoiding the use of ethanol as a solubilizer. The solubility of NM was also increased by dissolving it in the oil phase. The particle size distribution, zeta potential, entrapment efficacy and assay of the NM-loaded LMs were found to be 188.2 ± 5.4 nm, ,31.6 mV, 94.2% and 1.04 mg mL,1, respectively. The preparation was stable for 1 year at 4,10°C. The formulation and some physicochemical properties of NM-loaded LMs were investigated. The pharmacokinetic and biodistribution studies were performed in rats at a dose of 1.2 mg kg,1. From the observed data, there is no obvious retention of NM-loaded LMs in plasma. Moreover, incorporation of NM in LMs did not alter the tissue distribution significantly except for the relatively greater drug accumulation in the liver and spleen. The stimulation studies demonstrate that LMs of NM reduce irritation markedly compared with NM solutions. These results suggest that the LM system is a promising option to replace NM ethanol solutions as an intravenous treatment. [source]


Liver-targeted doxorubicin: effects on rat regenerating hepatocytes

LIVER INTERNATIONAL, Issue 3 2004
Giuseppina Di Stefano
Abstract: Background/Aims: The conjugate of doxorubicin (DOXO) with lactosaminated human albumin (L-HSA) has the potential of improving DOXO efficacy in the treatment of hepatocellular carcinomas (HCCs) expressing the asialoglycoprotein receptor (ASGP-R). In view of an adjuvant chemotherapy with L-HSA,DOXO after the surgical removal of the tumour, in the present experiments we verified whether DOXO accumulation produced by the conjugate can impair the liver regeneration following hepatic resection in non-cirrhotic liver. Methods: Using saline-injected hepatectomised rats as controls, we studied the effects of the conjugate on the ultrastructure of regenerating hepatocytes and evaluated [3H]thymidine incorporation, mitotic index and rate of DNA recovery in the liver remnant. Results: L-HSA,DOXO caused a selective drug accumulation in liver remnant, with low DOXO levels in extra-hepatic tissues. It did not change the ultrastructure of hepatocytes and did not increase serum alanine aminotransferase. It decreased [3H]thymidine incorporation and mitotic index, causing a moderate delay in hepatic DNA recovery. Conclusions: The experiments indicate a substantial resistance of rat regenerating hepatocytes to high intracellular concentrations of DOXO. They support the possibility of using L-HSA,DOXO in an adjuvant chemotherapy after the surgical removal of HCCs which maintain the ASGP-R. [source]


Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2009
Holger Fuchs
Abstract BI 1356 (INN: linagliptin) is an inhibitor of dipeptidyl peptidase-4 (DPP-4). This study investigated whether saturable binding of BI 1356 to its target DPP-4 occurs in tissues and whether drug accumulation occurs at these sites in vivo. In order to test these hypotheses, the tissue distribution of BI 1356 was determined in wild-type and DPP-4 deficient rats at different dose levels by means of whole body autoradiography and measurement of tissue radioactivity concentrations after single i.v. dosing of [14C]-radio labeled BI 1356. The accumulation behavior of drug-related radioactivity in tissues was further explored in an oral repeat dose study. Tissue levels of [14C]BI 1356 related radioactivity were markedly lower in all investigated tissues of the DPP-4 deficient rats and the difference of the dose-dependent increase of radioactivity tissue levels between both rat strains indicates that tissue distribution at low doses of BI 1356 is dominated by binding of BI 1356 to DPP-4 in tissues. As the binding to DPP-4 is strong but reversible, the tissue binding results in a long terminal half-life in several tissues including plasma. The binding capacity to DPP-4 is, however, limited. In the rat, saturation of DPP-4 binding is suggested at an intravenous dose above 0.01,0.1,mg/kg [14C]BI 1356. As the DPP-4 binding capacity is saturated already at low doses, accumulation of BI 1356 in tissues is unlikely, despite the long persistence of low amounts in the body. Copyright © 2009 John Wiley & Sons, Ltd. [source]


Decrease in Tumor Apparent Permeability-Surface Area Product to a MRI Macromolecular Contrast Medium Following Angiogenesis Inhibition with Correlations to Cytotoxic Drug Accumulation

MICROCIRCULATION, Issue 5 2004
HEIKE E. DALDRUP-LINK
ABSTRACT Background: New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (KPS) in tumors to a macromolecular contrast medium (MMCM), to follow changes in KPS induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin. Methods: Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)30) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate KPS. These estimates of KPS were correlated with cytotoxic drug accumulations in the tumors. Results: Anti-VEGF treatment reduced KPS to MMCM in tumor tissue from 0.013 mL h,1 cm,3 (n = 9) at baseline to 0.003 mL h,1 cm,3 (n = 9) 24 h later (p < .05). The KPS values correlated significantly (r2 = .78; p < .0001) with the tumor cisplatin accumulation. No correlation (r2 = .001; p = .89) was found between KPS and tumor accumulation of the substantially smaller 5-FU molecule. Conclusions: MMCM-enhanced MRI can be used to detect and estimate changes in KPS to this contrast agent following a single dose of anti-VEGF antibody. The decline in KPS induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration. [source]