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Transmucosal transport of tobramycin incorporated in solid lipid nanoparticles (SLN) after duodenal administration to rats. Part II--tissue distribution.

Tobramycin-loaded solid lipid nanoparticles (SLN) were prepared and administered by duodenal and intravenous (i.v.) routes to rats and the tissue distributions were determined successively at fixed times (30 min, 4 h and 24 h) and compared to those of the tobramycin solution after i.v. administration. The tissue distribution between tobramycin-loaded SLN administered duodenally and i.v. was different. A marked difference between tobramycin-loaded SLN administered duodenally and tobramycin solution administered i.v. was also evidenced. In particular, the amounts of tobramycin in the kidneys after tobramycin-loaded SLN administration either duodenally or i.v. were lower than after administration of i.v. solution. Tobramycin-loaded SLN were able to pass across the blood-brain barrier in rats to a greater extent after i.v. injection than after duodenal administration.

Animals↗

[Tissue distribution of 9, 3"-diacetylmidecamycin in the pregnant rat and in the rat following repeated administration (author's transl)].

The tissue distribution of 9, 3"-diacetylmidecamycin (MOM) was studied in the pregnant rats and in the rats following repeated administration. After oral administration of MOM (200 mg/kg) in the pregnant rats, the levels in the placenta and in the uterus were 2-3 times higher than that in the blood, however the levels in the amniotic fluid and in the fetus were 1/10-1/20 of the blood levels. After the third administration of MOM in the first day (30 mg/kg p.o./dose, 3 times/day, 4-hour interval), the levels in the liver, kidney, lungs, spleen, salivary glands and thymus were 1.5-12 times higher than that in the blood; the level in the muscle was almost equal to that in the blood; and the levels in the brain were 1/3-1/10 of the blood level. The tissue distribution patterns after repeated administrations were found to be similar to those of the first day administrations.

Animals↗

Tissue distribution of radioiodinated neoglycoproteins and mammalian lectins.

Quantitation of tissue distribution of radioiodinated neoglycoproteins 1 h after intravenous injection into mice allowed to evaluate their suitability to uncover potential selectivity in tracer retention. Variations within the panel of neoglycoproteins were introduced to the carbohydrate determinant, its density and linkage to the carrier. Five arrays of neoglycoproteins, encompassing up to twelve different carbohydrate moieties were used. The individual response on the level of organ content showed differences, accounted for by carbohydrate structure and density. However, increase in sugar density eventually caused general decrease in tissue retention, emphasizing the importance of synthetic parameters. Attachment of sugar residues to the spacer via primarily the C-6 group of monosaccharides led to rather prolonged survival in circulation of the resulting neoglycoprotein compared to the application of neoglycoproteins with p-aminophenyl glycosides as derivatives for coupling. Besides applying neoglycoproteins tissue uptake was also measured for several organs, when four mammalian lectins were employed as radiotracers. These lectins bind to cellular carbohydrate ligands, namely beta-galactosides, alpha-fucosides or heparin. Differences were measured for retention in liver, kidneys, spleen, stomach, thymus and bone marrow. The distinct properties of different tissues with respect to binding of neoglycoproteins as well as to endogenous lectins, exhibiting a certain degree of selectivity, are a step within the framework to attempt to therapeutically exploit the carrier potential of probes by recognitive protein-carbohydrate interactions.

Animals↗

Comparative pharmacokinetics and tissue distribution of the d-enantiomers of para-substituted methylphenidate analogs.

A comparative study of the plasma pharmacokinetics and tissue distribution of the d-threo enantiomers of methylphenidate (MPH), para-bromomethylphenidate (p-Br MPH), and para-methoxymethylphenidate (p-OCH3 MPH) was conducted in rats after i.p. administration of a 37 micromol/kg dose. The plasma kinetic data was fit to a two-compartment model with absorption and lag time as well as evaluated by noncompartmental methods. All three compounds attained maximal concentration within 10 min of injection. Calculated mean residence time and elimination half-life values for d-p-Br MPH were significantly longer than those for d-MPH and d-p-OCH3 MPH, and clearance of the bromo derivative was substantially lower than the latter two compounds. Tissue distribution studies of the three d-threo enantiomers revealed that para-substitution of d-MPH had a profound effect on the distribution pattern of these drugs. The highest concentration of drug was found in the kidney and lung for d-MPH, lung and liver for d-p-Br MPH, and lung and brain for d-p-OCH3 MPH. The bromo derivative was found in the highest concentration in the central nervous system at 30, 120, and 180 min whereas levels of d-MPH were twice as high as d-p-OCH3 MPH at 30 min but slightly lower than the latter at 120 min. Related studies on the lipophilicity, plasma protein binding, and resistance to plasma degradation of these compounds were also conducted. The combined data from these experiments along with the pharmacokinetics and central nervous system distribution of these drugs provide explanations for discrepancies between the in vivo and in vitro activity of these compounds described in previous work.

Animals↗

Comparative autoradiographic investigations on the tissue distribution of benfotiamine versus thiamine in mice.

The tissue distribution of two therapeutically applied preparations of B-vitamins were investigated in blood and selected organs (liver, brain, muscle, kidney) of laboratory mice using autoradiographic techniques. Incorporation of lipid-soluble 3H-benfotiamine (CAS 22457-89-2) and water-soluble 3H-thiaminehydrochloride (CAS 67-03-8) (200 microCi, equivalent to 105 mg vitamin/kg body weight) was monitored between 0.75 and 168 h after an oral or subcutaneous administration. The labelled tissue slices were autoradiographically analysed after a differential histochemical extraction procedure to evaluate the respective total radioactivity, the uptake into lipid-soluble, water-soluble and residual macromolecular compounds. Evaluation of these autoradiographic data (given as mumol vitamin preparation/mg tissue equivalent) proved that benfotiamine is incorporated much better than thiaminehydrochloride independent of the administration mode. In muscle and brain tissue a 5 to 25 fold higher amount of tracer incorporation was registered following benfotiamine as compared with the thiamine application, whereas in all other organs the difference in the label was mostly between 10 and 40%. Concerning the organ specific distribution, liver and kidney were the structures labelled highest by both substances and administration procedures. In the liver, concerning all incorporation times, a higher proportion of residual macromolecular compounds was found, whereas in the kidney the proportions of lipid- as well as of water-soluble materials prevailed. These data should be clinically relevant.

Adjuvants, Immunologic↗

Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease.

OBJECTIVE: Central adiposity, a component of insulin resistance syndrome, is a risk factor for nonalcoholic fatty liver disease (NAFLD) in adults. To determine whether a similar relationship occurs in children, hepatic fat content and adipose tissue distribution were assessed in obese children at risk for NAFLD. METHODS: We reviewed the charts of obese children undergoing evaluation for NAFLD because of hepatomegaly or elevated serum alanine aminotransferase (ALT) without obvious etiology. Hepatic fat fraction and adipose tissue distribution were obtained by rapid magnetic resonance imaging (MRI) techniques. Hepatic fat content was determined by a modification of the Dixon method that involves fast gradient echo. Body fat distribution was assessed by using heavily T1-weighted fast gradient echo technique on a single slice at the level of the umbilicus, and regions of interest were demarcated based upon pixel intensity threshold value including visceral adipose tissue (VAT) and subcutaneous adipose tissue content (SAT). RESULTS: Ten children underwent hepatic MRI only. Twenty-nine children underwent hepatic and adipose tissue distribution MRI. There was a correlation between hepatic fat fraction and VAT (r = 0.37, P < 0.05) but not body mass index or SAT. Elevated serum ALT was associated with a higher hepatic fat fraction (P < 0.001) and VAT (P = 0.06). CONCLUSION: Visceral adiposity is a risk factor for pediatric NAFLD.

Abdominal Fat↗

Iodine and/or selenium deficiency alters tissue distribution pattern of other trace elements in rats.

Tissue distribution of Fe, Mn, Cu, and Zn, the essential trace elements associated with oxidant and/or antioxidant processes, was examined in iodine- and/or selenium-deficient rats (ID, SeD, ISeD). Fe and Mn were the most affected minerals in all types of deficiency states. Mn levels decreased significantly in the liver in all deficiency states (approx 20-30%), in the heart in ID and SeD rats (approx 30-35%) and in the testis in ID rats (approx 15%). Whereas Mn enhancement was noted in kidney (approx 45%) and plasma in SeD and ISeD (approx 20% and 50%, respectively) animals. However, most striking alterations were seen with Fe. Significant elevation of Fe concentrations were observed in all deficiency states in the kidney (approx 90-125%) and heart (approx 20-25%), and in the liver in SeD (approx 35%) and ISeD (approx 75%) rats, whereas significant (approx 20%) Fe enhancement in the testis was observed only in ISeD animals. Lower Cu (approx 10-15%) and higher Zn (approx 10-20%) concentrations in heart tissues in all deficiency states were found; higher Zn (approx 20-35%) in the kidney of SeD and ISeD rats, and lower Cu in the testis of SeD animals were observed. In brain tissue, no alteration was seen in Fe, Mn, and Zn content, however, significantly increased (approx 15-20%) Cu concentrations were noted in all deficiency states. The results of this study indicated that iodine and/or selenium deficiency may modify the distribution and the homeostasis of other minerals.

Animals↗

The effects of thiamin on the tissue distribution of lead.

The effects of thiamin on the tissue distribution of lead were evaluated in Sprague-Dawley rats exposed to 1000 ppm lead acetate in drinking water and treated daily with thiamin (25 or 50 mg kg-1 body weight, i.p.), calcium ethylenediamine tetraacetic acid (50 mg kg-1 body weight, i.p.) or their combination for 8 weeks. The subtoxic dose of lead did not alter weight gains, feed and water consumption during the treatment period. Thiamin decreased the blood (P less than 0.0001), liver (P less than 0.0001) and kidney (P less than 0.0001) concentrations of lead. Thiamin (50 mg kg-1 body weight) reduced the lead concentrations in tissues more effectively than thiamin (25 mg kg-1 body weight). The combined treatment was more effective than the respective individual treatments.

Animals↗

Tissue distribution of 14C-indoprofen in the rat.

The tissue distribution of 14C-labelled 2-[p-(1-oxo-2-isoindolinyl)phenyl)propionic acid (indoprofen) after i.v. injection was studied in male and pregnant rats by whole-body autoradiography. Distribution was characterized by a rapid localization in the liver, kidneys and lungs. A significant amount of radioactivity found in the intestinal contents suggested biliary excretion. There was no indication of retention of the drug in the brain. In pregnant rats, radioactivity crossed the blood-placenta barrier to a moderate extent and low concentrations were found in foetuses.

Animals↗

Pharmacokinetic and tissue distribution changes of adriamycin and adriamycinol after intravenous administration of adriamycin to alloxan-induced diabetes mellitus rats.

The pharmacokinetic and tissue distribution changes of adriamycin (ADM) were investigated after intravenous (i.v.) administration of ADM, 16 mg/kg, to the control rats and alloxan-induced diabetes mellitus rats (AIDRs). After 1 min i.v. infusion of ADM, apparent 'constant' plasma levels of ADM were maintained from 2 to 12 h in the AIDRs, whereas the levels were detected only up to 3 h in the control rats. Adriamycinol was detected only up to 1 and 5 min for the control rats and AIDRs, respectively, with significantly higher levels in the AIDRs. In tissue distribution studies, the amount of ADM obtained from the heart, lung, stomach, liver, small intestine, large intestine, fat, and lymph nodes were significantly higher in the AIDRs than that in the control rats. The tissue to plasma ratios of the liver, fat, and muscle also increased significantly in the AIDRs than those in the control rats. The amount of adriamycinol obtained from the lung, kidney, and liver was significantly higher in the AIDRs. All 7 control rats survived longer than 48 h, however 7 out of 9 AIDRs died between 36-48 h after i.v. administration of ADM, suggesting that the i.v. doses. of ADM in diabetes mellitus patients may need to be modified if the present rat data could be extrapolated to human.

Animals↗

Autoradiography of tissue distribution of the IIA constituent of the pristinamycins.

The tissue distribution of a radioactive analogue of the IIA constituent of the pristinamycins was studied in female mice by autoradiography. Examination of slides and photographs discloses the presence of the antibiotic on the skin and in the bone marrow only a short time after injection. Elimination of the antibiotic is quick and is mainly through the digestive tract.

Animals↗

Pharmacokinetics, tissue distribution, and stability of antisense oligodeoxynucleotide phosphorothioate ISIS 3466 in mice.

Phosphorothioate oligonucleotides have a potential as therapeutic agents. The pharmacokinetics, tissue distribution, stability, and cellular uptake by LOX ascites tumor of p120 antisense phosphorothioate oligonucleotide, ISIS 3466, were studied in vivo. The oligonucleotide, which was quickly cleared from the circulation in the normal mice after IV injection, was readily absorbed into the systemic circulation from the peritoneum. The oligonucleotide was found in most tissues 48 h after IP administration. The highest concentrations were in kidney and liver, but the brain had a very low concentration. The phosphorothioate oligonucleotide was intact even after 48 h. When the oligonucleotide was complexed with cationic lipid DOTMA, the DOTMA did not affect the oligonucleotide uptake or tissue distribution in normal mice. However, DOTMA significantly increased the oligonucleotide cellular uptake (4-10 times) in LOX ascites tumors in an IP/IP model. These results indicate that the phosphorothioate oligonucleotide is stable, has favourable kinetics for use as an therapeutic agent, and that DOTMA could be useful in local delivery of the oligonucleotide in vivo.

Animals↗

Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats (II).

The objective of this study is to perform kinetic modelling of the tissue distribution of doxorubicin encapsulated into liposomes (L-DXR), especially to the heart and liver. The release process of doxorubicin (DXR) from liposomes in blood was quantified by a release clearance. This parameter defines a release rate of DXR based on the concentration of L-DXR in blood and was estimated from kinetic modelling of DXR distribution to the heart after L-DXR administration. The distribution of free DXR to the heart was modelled separately. The experimental data for this modelling were reported previously (Harashima et al., Biopharm. Drug. Disposit., 13, 155-170 (1992)). This analysis provided a free DXR concentration profile as well as a release clearance of DXR after L-DXR administration. There was a remarkable difference in the free DXR concentration in blood between free and liposomal administration. The area under the DXR curve in the heart was reduced by approximately one third from that for the first two hours after DXR administration by liposomal encapsulation, which could be the reason for reduced cardiac toxicity. In our previous report, the distribution of L-DXR to the liver was shown to be explained by a sequentially linked two-compartment model with efflux process. The validity of this efflux model was examined in this study by a repeated dose study. The apparent uptake clearance decreased with time and showed a second peak after the repeated dose, which justified the efflux model. These kinetic analyses give quantitative understanding of the effect of liposomal encapsulation on the tissue distribution of DXR.

Animals↗

[Preparation of albendazole polybutycyanocrylate nanoparticles and study on its pharmaceutical properties and tissue distribution].

AIM: To prepare the target drug delivery systems(TDDS), albendazole polybutycyanocrylate nanoparticles (ABZ-PBCA-NP), its pharmaceutical characters and tissue distributions were simultaneously investigated. METHODS: Albendazole nanoparticles were prepared with the emulsification-polymerization method and the drug-load mechanism of polybutycyanocrylate nanoparticles was studied with the equal-tempaerature adsorption principle. The dialyse dynamic of albendazole from ABZ-PBCA-NP was investigated in four formulations in vitro. The tissue distribution of albendazole in different drug vehicles was studied with isotope labelling experiment. RESULTS: ABZ-PBCA-NP and ABZ-PVP-PBCA-NP fit to the Higuchi and bi-exponent function in vitro respectively. The drug loaded in nanoparticles was abide by the Langmuir adsorption equation. Targeting index of albendazole in liver and spleen in mice are 11.4 and 3.9 after ig 3H-ABZ-PBCA-NP. The bioavailability of albendazole nanoparticle and suspension are 76.0% and 36.9% respectively. CONCLUSION: The absorptive capability of drug was enhance when 4% PVP was added into the nanoparticle, and its release time was lengthen. At the same time, the nanoparticles vehicles increase the albendazole bioavailability.

Albendazole↗

Disposition and tissue distribution of angiopeptin in the rat.

The disposition and tissue distribution of angiopeptin, a long-acting octapeptide analogue of somatostatin, were studied in rats following single iv and sc administration of the drug. Similar plasma levels and excretion values of angiopeptin were observed by using radioimmunoassay and radiolabeling techniques. Angiopeptin was absorbed fairly rapidly, with a mean peak plasma level of 25 +/- 4.1 ng/ml at 10-15 min after administration. The kinetics of angiopeptin following sc administration closely resembled those following iv administration due to rapid absorption. The pharmacokinetics of angiopeptin can be described by a two-compartment model. The plasma half-life of the drug ranged from 2.6-2.9 hr when administered sc and 1.98-2.5 hr when given iv. Distribution of angiopeptin was rapid, with the highest concentration appearing in the liver. Half-lives in the liver and bile were short. Most of the drug was excreted in the feces via the bile, while approximately 10% was excreted in the urine. Angiopeptin was also found to be secreted in the saliva. TLC and HPLC of blood, urine, feces, and bile samples did not reveal the presence of any metabolites. In conclusion, the in vivo fate of angiopeptin is characterized by little or no hepatic metabolism and rapid biliary excretion.

Amino Acid Sequence↗

Diazinon toxicokinetics, tissue distribution and anticholinesterase activity in the rat.

The toxicokinetics, tissue distribution, and anticholinesterase (antiChE) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after i.v. administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following i.v. and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailability was found to be low (35.5%). Hepatic extraction ratios after i.v. administration of 5 or 10 mg/kg were 54.8% and 47.7%, respectively, suggesting that low systemic oral bioavailability can be explained by a first-pass effect in the liver. Diazinon was found to be approximately 89% protein-bound in plasma within the concentration range 0.4-30 ppm. The highest concentration of diazinon after i.v. administration was found in the kidneys, when comparing to liver, kidney, brain. Both red blood cell (RBC) acetylcholinesterase (AChE) and plasma ChE activities were inhibited rapidly (44% and 17% at 10 min, and 36% and 13% min for i.v. and oral administration, respectively), but inhibition of RBC AChE was greater than that of plasma ChE.

Acetylcholinesterase↗

HPLC study of tissue distribution of loganin in rats.

A rapid, sensitive and selective high performance liquid chromatography (HPLC) method was developed and validated for determination of loganin in rat tissues. Samples were prepared based on a simple protein precipitation. Separation of loganin was achieved on a reversed-phase C(18) column (250 x 4.6 mm, 5 microm) with a mobile phase consisting of acetonitrile and water (16:84, v/v) at a flow rate of 1.0 mL/min. The detection wavelength was set at 236 nm and the temperature of the column was kept at 30 degrees C. The method was applied to study tissue distribution of loganin in rats after a single administration of loganin at a dose of 20 mg/kg. The highest level was observed in kidney, then in stomach, lung and small intestine. The lowest level was found in brain. The peak levels were attained at 90 min in most tissues. It was indicated that kidney was the major distribution tissue of loganin in rats, and that loganin had difficulty in crossing the blood-brain barrier. It was also found there was no long-term accumulation of loganin in rat tissues.

Animals↗

Tissue distributions of CYP2D1, 2D2, 2D3 and 2D4 mRNA in rats detected by RT-PCR.

The tissue distributions of four isoforms (CYP2D1/5, 2D2, 2D3 and 2D4/18) in rat CYP2D subfamily were investigated. Twelve kinds of tissue (liver, kidney, brain, lung, heart, spleen, adrenal gland, small intestine mucosa, bladder, testis, ovary and gonecystis) were removed from Sprague-Dawley male and female rats. The expression of CYP2D mRNA in these tissues was detected by RT-PCR. Specific primers were designed to recognize the four isoforms individually. In liver, kidney and small intestine mucosa, the mRNA expression of all four CYP2D isoforms was detected as high-intensity PCR products. mRNA of CYP2D1/5 was expressed in all tissues used in this study except the brain, although the intensity of PCR products varied among tissues. mRNAs of CYP2D2 and CYP2D3 were mainly expressed in liver, kidney and small intestine mucosa, which were exposed to xenobiotics such as drugs, food components and environmental contaminations. mRNA of CYP2D4/18 was expressed in liver, kidney, small intestine mucosa and brain. In brain, only mRNA of CYP2D4/18 was expressed. CYP2D4/18 mRNA was also expressed in ovary, testis and gonecystis. The tissue distributions help to clarify the differences in physiological and pharmacological functions between CYP2D isoforms.

Animals↗