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PubMed2006

Radiochemical synthesis and tissue distribution of p-[18F]DMPPF, a new 5-HT1A ligand for PET, in rats.

Several studies have demonstrated the potential of p-[(18)F]MPPF as a radiopharmaceutical to study the 5-HT(1A) receptor family in animals and humans. A structural modification leading to a higher radioactive signal at an equipotent dose would greatly enhance this potential. With this goal, the desmethylated 4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]-piperazine (p-MPPF), identified as p-DMPPF, was synthesized, labeled with fluorine-18 and evaluated through ex vivo tissue distribution in rats. The new compounds p-DMPPF, p-DMPPNO(2), MEM-p-MPPF and MEM-p-MPPNO(2) were isolated and fully identified ((1)H and (13)C NMR, LC-MS). The final compound, p-[(18)F]DMPPF, was obtained ready for injection, with an overall radiochemical yield of 10% (EOB corrected) within 90 min and a specific activity of 62 GBq/mumol. Tissue distributions showed that the carbon-fluorine bond was stable in vivo and that this compound could cross the blood-brain barrier. For kidney, lung, heart, spleen, bone, testicle, liver and muscle, the percentage of injected dose per gram of tissue obtained with p-[(18)F]DMPPF was of the same order of magnitude as that of p-[(18)F]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[(18)F]DMPPF compared with p-[(18)F]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT(1A) receptors in rats. The radioactivity increase was more important for specific tissues (hippocampus and frontal cortex) than for cerebellum or striatum, leading to better contrast (hippocampus/cerebellum=5.8 at 60 min). The levels of metabolites found in plasma showed that p-[(18)F]DMPPF appears to be less metabolized than p-[(18)F]MPPF. p-[(18)F]DMPPF deserves further evaluation as a radiopharmaceutical candidate.

Animals↗

PubMed1985

Tissue distribution of amiodarone and desethylamiodarone in rats after repeated oral administration of various amiodarone dosages.

Tissue distribution of amiodarone (Cordarone) and desethylamiodarone in the rat was investigated after repeated oral application of various dosages of the drug. Serum and tissue concentrations ofBamiodarone and desethylamiodarone were assessed by high-performance liquid chromatography. The amiodarone and desethylamiodarBne serum and tissue levels obtained after repeated oral application of doses ranging from 25 to 100 mg/kg reveal that the accumulation of amiodarone and desethylamiodarone in the rat is dose-dependent. Amiodarone is preferentially distributed in decreasing order in adipose tissue, lung, thyroid gland, kidney and liver whereas its metabolite shows the highest affinity for lung then followed by kidney, thyroid gland, adipose tissue and liver. The penetration of amiodarone and desethylamiodarone into brain was poor and with all the applied dosages brain levels were in the same range as the corresponding serum levels. Desethylamiodarone serum and tissue concentrations were consistently lower than the corresponding amiodarone concentrations and varied from 5 to 78% (mean 45%) depending on the dose administered and the kind of tissue. The amiodarone tissue/serum concentration ratios were very high in adipose tissue (220-340) and moderate to high in the other tissues except brain (3-100) and indicate an extensive distribution of the drug with fat as a depot with a large storage capacity. The desethylamiodarone tissue/serum concentration ratios were very high in lung tissue (50-620), high in renal, thyroid and adipose tissue (20-390) and moderate in the other tissues except brain (3-90), respectively, and indicate an extensive distribution of the metabolite with fat as a reservoir and lung, kidney and thyroid gland, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed2002

Oxycontin: the concept of a "ghost pill" and the postmortem tissue distribution of oxycodone in 36 cases.

Oxycodone is a semi-synthetic opioid that is structurally similar to codeine and equipotent to morphine in producing analgesic effects. Oxycodone has been prescribed in many immediate-release formulations including Percodan, Percocet, Tylox, Roxicodone, and Toxicet. In 1995, the Food and Drug Administration approved Oxycontin, a controlled-release form of oxycodone. Although the immediate-release forms of oxycodone can be prescribed in doses of 10-30 mg every 4 h, it is recommended that Oxycontin be prescribed in doses of 10-160 mg every 12 h. In a six-year period, the Los Angeles County Department of Coroner's Toxicology Laboratory detected oxycodone in 67 cases, 36 of which were determined to be the controlled-release form. The objectives of this paper are to provide general information about Oxycontin, including postmortem tissue distributions of oxycodone in cases in which the controlled-release form was identified, and to introduce the concept of ghost pills. A ghost pill is a seemingly intact but drug-free tablet that resembles an undigested pill. The isolation and identification of oxycodone from postmortem specimens was achieved using a basic, liquid-liquid extraction with screening and quantitation by gas chromatography-nitrogen-phosphorus detection and gas chromatography-mass spectrometry, respectively. Oxycodone-d3 was used as an internal standard for quantitation. The assays were linear from 0.10 to 5.0 mg/L. The tissue distribution ranges of oxycodone in the 36 case examples were heart blood 0.12-46 mg/L (36), femoral blood + < 0.10-13 mg/L (35), liver 0.11-6.1 mg/kg (16), urine 2.5-122 mg/L (22), bile 0.19-49 mg/L (15), vitreous 0.24-0.82 mg/L (6), and gastric 0.06-119 mg total (21).

Adult↗

PubMed1975

Comparative antihypertensive effects and tissue distribution of beta adrenergic blocking drugs.

The precise mechanism of the antihypertensive action of beta adrenergic blocking drugs is not known. Both peripheral and central sites of action have been proposed. The comparative antihypertensive actions and tissue distribution of propranolol, pindolol and sotalol were investigated in both normotensive Sprague-Dawley and spontaneously hypertensive rats. From recordings of concurrent changes in blood pressure and heart rate it was observed that oral or subcutaneous administrations of both propranolol and pindolol, but not sotalol, consistently reduced blood pressure and heart rate. Tissue distribution of all three agents was determined after 14 days of treatment. Propranolol and a metabolite were concentrated in the hippocampus whereas pindolol was concentrated in the septum. Significant central concentrations of sotalol were not demonstrable. All three agents produced persistent peripheral beta adrenergic blockade. It is concluded that beta adrenergic blockade may not be the important mechanism of the antihypertensive action of beta adrenergic blocking drugs. A modification of central autonomic control mechanisms is proposed as a possible mechanism of action.

Administration, Oral↗

PubMed1977

Retention and tissue distribution of 210Pb (NO3)2 administered orally to infant and adult monkeys.

The retention and tissue distribution of 210Pb were studied in 10-day-old, 150-day-old, and adult monkeys. Lead-210 nitrate was administered to the monkeys by gavage after a 12 hr fast and 210Pb excreted in urine and feces was monitored for 96 hr. All monkeys were necropsied 96 hr after dosing and the 210Pb concentrations of various tissues was determined. The data demonstrated that infant monkeys retained 64.5 and 69.8% of the orally administered 210Pb at 10 and 150 days of age, respectively, while adult monkeys retained 3.2% of the 210Pb dose. Blood 210Pb levels 96 hr after dosing did not vary significantly between age groups. Of the 210Pb contained in blood, 98-99% was found in blood cells and 1-2% in blood plasma; 5-8% of the Pb in blood cells was bound to blood cell membranes. None of these parameters varied significantly with age. The percentage of the lead dose excreted in urine did not vary significantly between age groups. Analysis of tissues for 210Pb revealed that both the tissue Pb concentrations and tissue Pb:blood Pb ratios were significantly higher in the bone structure of infants than adults. Brain Pb:blood Pb ratios were significantly greater in 10-day-old infants than 150-day-old infants or adults.

Administration, Oral↗

PubMed1997

Tissue distribution and macromolecular binding of extremely low doses of [14C]-benzene in B6C3F1 mice.

The tissue distribution and macromolecular binding of benzene was studied over a dose range spanning nine-orders of magnitude to determine the nature of the dose-response and to establish benzene's internal dosimetry at doses encompassing human environmental exposures. [14C]-Benzene was administered to B6C3F1 male mice at doses ranging between 700 pg/kg and 500 mg/kg body wt. Tissues, DNA and protein were analyzed for [14C]-benzene content between 0 and 48 h post-exposure (625 Ng/kg and 5 microg/kg dose) by accelerator mass spectrometry (AMS). [14C]-Benzene levels were highest in the liver and peaked within 0.5 h of exposure. Liver DNA adduct levels peaked at 0.5 h, in contrast to bone marrow DNA adduct levels, which peaked at 12-24 h. Dose-response assessments at 1 h showed that adducts and tissue available doses increased linearly with administered dose up to doses of 16 mg/kg body wt. Tissue available doses and liver protein adducts plateau above the 16 mg/kg dose. Furthermore, a larger percentage of the available dose in bone marrow bound to DNA relative to liver. Protein adduct levels were 9- to 43-fold greater than DNA adduct levels. These data show that benzene is bioavailable at human-relevant doses and that DNA and protein adduct formation is linear with dose over a dose range spanning eight orders of magnitude. Finally, these data show that the dose of bioactive metabolites is greater to the bone marrow than the liver and suggests that protein adducts may contribute to benzene's hematoxicity.

Animals↗

PubMed2000

11Beta-hydroxysteroid-dehydrogenase isoforms: tissue distribution and implications for clinical medicine.

11Beta-hydroxylation is essential for glucocorticoid and mineralocorticoid activity of a steroid. The enzyme catalyzing this reaction is termed 11beta-hydroxysteroid-dehydrogenase (11beta-HSD). Two isoenzymes of 11beta-HSD have been characterized in human tissues. Whereas 11beta-HSD-I works mainly as a reductase, 11beta-HSD-II only functions as an oxidizing (inactivating) enzyme for physiological glucocorticoids. Thus, the tissue distribution of both enzymes plays a crucial role for the specific glucocorticoid status of an organ. This review summarizes our knowledge of tissue distribution of both 11beta-HSD isoenzymes, their physiological function and pathophysiological role in certain clinical abnormalities, and their relevance to the metabolism of synthetic glucocorticoid and mineralocorticoid compounds.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed1992

Tissue distribution, elimination, and metabolism of [3H]leukotriene C4 by the conscious marine toad, Bufo marinus.

Tissue distribution, elimination, and metabolism of 3H-labelled leukotriene (LT) C4 were studied in ureter-catheterized conscious marine toads, Bufo marinus. Six and 24 h after injection, organs containing the highest percent of injected radioactivity were small intestine, liver, and kidney. Radioactivity declined in these organs at 24 h by approximately threefold. Peak elimination time for radioactivity in the urine was between 2 and 4 h after the injection. During the 24-h collection period, 55.2 +/- 0.2% of the injected radioactivity was eliminated in the urine. Polar metabolites represented 40.3 +/- 1.1, 57.3 +/- 5.6, and 62.8 +/- 1.6% of the radioactivity at 2, 4, and 6 h, respectively. The primary urinary polar metabolite was 20-carboxy-LTE4, with 18-carboxydinor-LTE4 and 20-hydroxy-LTE4 also present. [3H]LTE4 decreased from 37.2 +/- 1.8% at 2 h to 15.8 +/- 3.3 and 15.0 +/- 2.1% of the radioactivity at 4 and 6 h, respectively. Bile radioactivity was low. N-Acetyl-LTE4 was not detected in urine or bile samples. Radioactivity in the pan water was 14.3 +/- 2.4 and 15.8 +/- 2.5% of the injected radioactivity, at 6 and 24 h, respectively, suggesting that the skin was a route for excretion of leukotrienes. The marine toad is an interesting model demonstrating both similarities and differences from mammals in distribution, elimination, and metabolism of peptide leukotrienes.

Animals↗

PubMed2001

Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice.

Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the extent and profile of tissue distribution of 14C-tolterodine, after single and repeat oral dosing, was investigated in the mouse. Overall, distribution of radioactivity in tissues was rapid, and there were no gender-specific differences. The concentration of radioactivity in most tissues was similar to, or exceeded, that in blood. Highest concentrations were measured in gall bladder, urinary bladder, liver, kidneys and lungs, while the lowest concentration (10-times lower than in plasma) was seen in the brain. The distribution pattern after repeat oral dosing was similar to that after a single dose, although the decline in tissue concentrations was slower. Studies in pregnant mice showed that the distribution of radioactivity differed between dams and fetuses. Radioactivity was low and showed homogeneous distribution in the fetus, while a heterogeneous pattern was seen in the dam. Highest concentrations were seen in the fetal liver, brain and spinal cord. Some accumulation was observed in the choroid plexus. Placental concentrations of radioactivity were generally higher than those in the fetus, with some accumulation in the yolk sac. Studies in suckling mouse pups showed low levels of exposure to drug-related radioactivity (around 0.2% of the dose); the milk:plasma concentration ratio was 0.0-0.7. In conclusion, tolterodine and its metabolites are rapidly distributed into tissues following oral administration of radiolabelled drug in the mouse, with many tissues (including the fetus) reaching similar concentrations to that observed in blood. In other tissues, especially the eliminating organs, radioactivity levels were much higher than in blood. Penetration of the central nervous system was low, suggesting that the risk of deleterious effects on cognitive function may be lower with tolterodine than with more lipophilic antimuscarinic drugs.

Animals↗

PubMedDate not supplied

Tissue distribution of different mercurial compounds analyzed by the improved FI-CVAAS.

Mercury contents in biological samples can be measured by cold vapor atomic absorption spectroscopy combined with the flow-injection analysis system. However, water vapor in the absorption cell attenuated and distorted the signals. This study described the strategy to overcome this problem by adding an additional gas-liquid separator after the mixing/separator assembly. This modification can efficiently minimize the moisture in the transfer line and in the absorption cell. This improved technique was adopted to study the differential tissue distribution of methylmercury and HgS after oral administration to mice for five consecutive days. The present study suggests that the insoluble HgS (the main constituent of a Chinese mineral drug, cinnabar, used as a sedative) can still be absorbed from gastrointestinal tract and distributed to various tissues including the brain. As compared with methylmercury, the total amount of HgS accumulated in the tissues ranging about one five-thousandth of methylmercury, which is well correlated with the biological activity of HgS reported previously.

Administration, Oral↗

PubMed1976

Tissue distribution and characteristics of xanthine oxidase and allopurinol oxidizing enzyme.

Tissue distribution and levels of allopurinol oxidizing enzyme and xanthine oxidase with hypoxanthine as a substrate were compared with supernatant fractions from various tissues of mice and from liver of mice, rats, guinea pigs and rabbits. The allopurinol oxidizing enzyme activities in liver were quite different among the species and the sex difference of the enzyme activity only in mouse liver. In mice, the highest activity of allopurinol oxidizing enzyme was found in the liver with a trace value in lung, but the enzyme activity was not detected in brain, small intestine and kidney, while the highest activity of xanthine oxidase was detected in small intestine, lung, liver and kidney in that sequence. The allopurinol oxidizing enzyme activity in mouse liver supernatant fraction did not change after storage at -20 degrees C or dialysis against 0.1 M Tris-HCl containing 1.15% KCl, but the activity markedly decreased after dialysis against 0.1 M Tris-HCl. On the contrary, the xanthine oxidase was activated 2 to 3 times the usual activity after storage at -20 degrees C or dialysis of the enzyme preparation. These results indicated that allopurinol was hydroxylated to oxipurinol mainly by the enzyme which is not identical to xanthine oxidase in vivo. A possible role of aldehyde oxidase involved in the allopurinol oxidation in liver supernatant fraction was dicussed.

Allopurinol↗

PubMed1997

Plasma pharmacokinetics, tissue distribution and excretion of MnDPDP in the rat and dog after intravenous administration.

PURPOSE: To investigate distribution and excretion of mangafodipir (MnDPDP, Teslascan) in the rat and dog. MATERIAL AND METHODS: Formulations of either 14C-MnDPDP or 54MnDPDP were injected intravenously at near clinical doses in rats and dogs. RESULTS: The manganese (Mn) moiety is rapidly removed from plasma with an elimination half-life of less than 25 min in both species, reflecting a rapid distribution to the tissues and an early excretion. The plasma clearance of the DPDP moiety is slower than that of Mn and it appears to distribute into the extracellular fluid. Mn is distributed largely to the liver, pancreas and kidneys, and in pregnant rats, also to foetal liver and bones. No transplacental passage of DPDP could be detected. The metal is mainly excreted by the faecal route, with a small fraction eliminated early in the urine. DPDP is rapidly and essentially completely excreted in the urine, consistent with the glomerular filtration rate. CONCLUSION: The ligand does not appear to facilitate the transport of Mn into any organ except the kidney for subsequent excretion, and it reduces distribution to the heart. The Mn is taken up by those organs indicated for MR imaging, primarily liver and pancreas.

Animals↗

PubMed1987

Tissue distribution of phenoxybenzamine in the rat. Lack of adipose tissue storage.

Rats were given the basic lipophilic drug, phenoxybenzamine, in single i.v. doses of 0.4 and 30 mg/kg. The drug was determined in plasma and 7 tissues by a new HPLC method. Adipose tissue reached peak levels after 30 minutes. At that time levels in heart, kidney, and brain were higher than in subcutaneous, epididymal, and mesenteric adipose tissues. The percentage metabolites in adipose tissue, kidney, and liver was 0, 88, and 96, respectively. Pretreatment with SKF 525-A inhibited metabolism and increased the tissue levels of unchanged drug, however, even under these conditions storage in adipose tissues did not occur, the adipose storage index being still less than unity. These results contradict findings of the 1950s which have been repeatedly reported in textbooks and reviews, but they confirm observations that basic drugs, even when highly lipophilic, are not being stored in adipose tissues.

Adipose Tissue↗

PubMed2006

[Influence of fat tissue distribution on metabolic complications in children and adolescents with simple obesity].

BACKGROUND: Increased prevalence of obesity in children and adolescents results in more common metabolic complications characteristic for adults, particularly those with abdominal obesity. The objective of the study was to determine the relation between the fat tissue distribution and metabolic complications and to estimate the prevalence of the metabolic syndrome in obese children and adolescents. MATERIAL AND METHODS: We studied 64 children (42 girls and 22 boys) with simple obesity (BMI =97 pc) in the mean age 12.4+/-3.4 years. The fat tissue distribution was assessed on the basis of waist circumference, hip circumference, waist to hip ratio (WHR) and skinfold thickness (suprailiac, subscapular, biceps and triceps). In all children plasma concentrations of total cholesterol, HDL and LDL cholesterol as well as triglycerides were estimated. Plasma glucose and insulin levels were measured in fasting state and during the oral glucose tolerance test (OGTT). Fasting insulin to glucose ratio (FIGR) was calculated. Blood pressure was measured in triplicate. RESULTS: In 33 (51.6%) of children dyslipidemia, in 10 (15.6%) hyperinsulinemia or impaired glucose tolerance and in 12 (18%) hypertension was diagnosed. The Metabolic syndrome was present in 9 (14%) children. The anthropometric predictor for the risk of metabolic complications was a greater waist circumference, while greater hip circumference decreased the risk. CONCLUSIONS: The metabolic complications characteristic of metabolic syndrome, previously diagnosed exclusively in adults, may occur also in obese children and adolescents. As in adults, abdominal obesity is the most relevant risk factor of the metabolic syndrome.

Adipose Tissue↗

PubMed1983

Kinetics of tissue distribution and elimination of 4,4'-methylene bis(2-chloroaniline) in rats.

The tissue distribution kinetics and elimination of 4,4'-methylene bis(2-chloroaniline) (MBOCA) in rats was studied after a single dose of [14C]MBOCA (0.49 mg/kg body weight, i.v.). The highest concentrations of radioactivity were in the small intestine, liver, adipose, lung, kidney, skin, and adrenals. For most tissues, a rapid decrease in radioactivity was followed by a slower decrease except for the small intestine, adipose and skin which demonstrated transient increases. Subcellular distribution in liver at 1 h showed radioactivity in all cell fractions. Although very lipophilic, [14C]MBOCA was completely eliminated within 48 h with the major route via the feces (73.4%).

Adipose Tissue↗

PubMed1995

Possible relationship between tissue distribution of DNA adducts and genotoxicity of food-derived heterocyclic amines.

During the past decade and a half, a number of potent mutagens belonging to the class of heterocyclic aromatic amines (HCA) have been isolated and identified from cooked fish, beef, fowl and other meat, and from beef extracts. Several of these HCA mutagens have also been found to be carcinogenic in rodent bioassays, and one of these compounds, 2-amino-3-methylimidazo-[4,5-f]-quinoline (IQ), has recently been found to cause hepatocellular carcinoma in cynomolgus monkeys. The potential etiological role of these mutagens and carcinogens in human cancer prompted us to evaluate the genotoxicity of these compounds in both nonhuman primates and rodents, with particular emphasis on the formation and tissue distribution of DNA adducts. We selected three compounds for this study based on several factors including chemical structure, mutagenic activity in vitro, concentration in cooked food, and carcinogenic activity in the rodent test system. These were IQ, 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (8-MeIQx), and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine (PhIP). To maximize the sensitivity of the DNA adduct measurements, we have employed the 32P-postlabeling method to analyze levels and tissue distribution of DNA adducts derived from IQ 8-MeIQx, and PhIP. We have measured DNA adduct formation for all three compounds in various tissues and white blood cells of monkeys following both acute and chronic administration. Both IQ and PhIP form high levels of adducts in a number of organs, particularly liver, kidney, and heart. In contrast, administration of 8-MeIQx to the cynomolgus monkeys results in the formation of only low adduct levels with many tissues showing no detectable levels of adducts. Studies in rodents have also shown that IQ and PhIP from DNA adducts in a number of organs in addition to those that are targets for carcinogenic effects of these agents. Although high DNA adduct levels of HCA are generally found in target organs for HCA induced carcinogenesis the widespread distribution of the adducts in organs not associated with the carcinogenic effects suggest that HCA exposure may be a possible etiological factor in cardiovascular diseases and other degenerative ailments.

Amines↗

PubMed1983

Tissue distribution of lead in the neonatal rat exposed to multiple doses of lead acetate.

The tissue distribution of lead (Pb) was examined in the neonatal rat intragastrically administered lead acetate (50 mg/kg, containing 210Pb) beginning on d 6 postpartum and thereafter at 3-d intervals to d 18. A time-dependent pattern of uptake was observed in bone, kidney, liver, and brain, while stomach, lung, heart, and spleen had no accumulation of Pb. The highest concentration of Pb at d 21 was detected in bone, and the least amount was found in blood and brain. Body weight was not significantly affected by the level of Pb exposure employed.

Animals↗

PubMed1979

[In vivo study of the effects of i.v. immunoglobulin therapy. Tissue distribution of native and enzyme-treated human immunoglobulin fractions given i.v. in man].

The tissue distribution of intravenously injected native and enzyme-treated human gammaglobulin has been investigated in human rectum mucosa. FITC-labelled antibodies to human gammaglobulin were used to locate the injected antibody preparation. Three hours after application of these different gammaglobulin-preparations no enrichment in the mucosa was found. Neither the native gammaglobulin nor the enzyme-treated gammaglobulin showed any concentration in the lamina propria of the large bowel mucosa or an intracellular enrichment in the epithel. This study shows that the quicker elimination of enzyme-treated gamma-globulin from the circulation cannot be explained by an intracellular increase.

Animals↗