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Absorption, excretion and tissue distribution of stable zinc and 65zinc in ponies.

Absorption excretion and tissue distribution of stable Zn and 65Zn in mature ponies were studied in three experiments. In the first experiment, the metabolism of stable, dietary Zn and intravenously administered 65Zn was studied in three ponies in a 3 X 3 Latin square design. The ponies were fed a corn and beet pulp diet containing 35 mg Zn/kg or the same diet with 250 or 520 mg of supplemental Zn as ZnO. The ponies absorbed and retained more stable Zn when fed 250 mg of supplemental Zn that when fed the basal diet alone or the basal diet plus 520 mg of supplemental Zn. The ponies retained more 65Zn (percentage of dose) when fed the basal diet or the same diet with 250 mg of supplemental Zn. The intestinal tract was the major route of excretion of stable Zn and 65Zn. In the second experiment, the retention of an oral dose of 65Zn was studied in three ponies in a 3 X 3 Latin square design. The ponies were fed a beet pulp, corn starch and alfalfa meal diet containing 15 mg Zn/kg or the same diet with 240 or 480 mg of supplemental Zn as ZnO. The ponies retained a greater percentage of a dose of 65Zn when fed the basal diet or the basal diet plus 240 mg of supplemental Zn than when fed 480 mg of supplemental Zn. In the third experiment, four ponies fed a commercial pelleted diet containing 125 mg Zn/kg were given an intravenous dose of 65Zn. The ponies were killed 7 to 14 days after receiving the dose and tissues were counted for radioactivity. Parenchymatous organs such as liver, pancreas, kidney, heart and lung contained a greater percentage of 65Zn than did structural organs such as bone and muscle. The wall of the gastrointestinal tract contained more radioactivity than did the contents.

Animals↗

Partial sequencing and tissue distribution of the canine isoforms of steroid 5alpha-reductase type I and type II.

BACKGROUND: The dog is regarded to be a valid model to test the effects of 5alpha-reductase inhibitors on prostatic growth. However, limited information is available on the characteristics or even existence of 5alpha-reductase isozymes in this species. METHODS: Here, we set out to clone the cDNA of the dog isoforms of 5alpha-reductase type I and type II by a degenerate cloning strategy and to assess the tissue distribution of both transcripts and the enzymatic activity of the isozymes. RESULTS: We identified two clones with homology to the human 5alpha-reductase isoforms type I and type II to be expressed in dog prostate. At the amino-acid level, these partial clones were found to exhibit a homology with their human counterparts of 83% and 88%, respectively. The expression levels of 5alpha-reductase mRNA were screened by RT-PCR in a number of dog tissues. No correlation was found between tissue mRNA expression and enzymatic 5alpha-reductase activities. CONCLUSIONS: The present study describes the partial cloning of the dog 5alpha-reductase isozymes and their tissue distribution. These results provide additional data for the use of the dog as an animal model to investigate the role of 5alpha-reductase isozymes in steroid metabolism.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Tissue distribution of [14C]ethambutol in mice.

Fifteen male mice were given oral doses of 32 mg [14C]ethambutol/kg in a study of the tissue distribution of the drug. Animals were killed 1, 2, 4, 7, and 24 h after dosage and radioactivity in various tissues was measured. Peak concentrations were seen at 2 h after dosage. With the exception of brain, all tissues examined (liver, kidney, heart, spleen, lung, and muscle) developed tissue-to-plasma concentration ratios greater than 2. Highest values were seen in liver, kidney, and lung. High lung values were viewed as a favorable attribute for a drug used in the treatment of tuberculosis.

Administration, Oral↗

Effects of intra-abdominal pressure on pharmacokinetics and tissue distribution of doxorubicin after intraperitoneal administration.

Increased hydrostatic pressure in solid tumor nodules decreases the penetration of chemotherapy into cancerous tissue. This is true for both i.v. and i.p. chemotherapy. The purpose of this study was to determine the influence of increasing intra-abdominal pressures on the pharmacokinetics and tissue distribution of doxorubicin administered i.p. Four groups of 10 Sprague Dawley rats were given i.p. doxorubicin (4 mg/kg) during 60 min combined with no pressure (control), 10, 20 and 30 mm Hg pressures. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled. Two other groups of 10 rats received the same dose of i.p. doxorubicin during 10 min combined with no pressure and 30 mm Hg pressure. At the end of experiments animals were sacrificed and tissue samples were collected. Doxorubicin concentrations in peritoneal fluid, plasma and tissues were determined by HPLC. Pharmacokinetic studies showed that increased intra-abdominal pressures of 10, 20 and 30 mm Hg did not alter peritoneal fluid AUCs, the plasma AUCs and the peak ratios of i.p. doxorubicin when compared to the control group (no pressure). A subset analysis of high intra-abdominal pressure groups (20 and 30 mm Hg) versus control group showed statistically significant differences in peritoneal fluid AUCs, plasma AUCs and AUC (peritoneal fluid/plasma) ratios. For all groups, the highest tissue concentrations of doxorubicin were found in tissues associated with the parietal peritoneum: the bladder, the abdominal wall and the diaphragm. After 10 min of i.p. chemotherapy, the group treated with 30 mm Hg pressure showed a significant increase of doxorubicin concentrations in these tissues as compared to the control group. This significant increase of tissue doxorubicin concentrations was not found after 60 min of pressure with i.p. chemotherapy; prolonged intra-abdominal pressure was associated with a high incidence of intestinal ischemia. In conclusion, intra-abdominal pressure of 20 and 30 mm Hg significantly decreased the AUC ratios of i.p. doxorubicin but concomitantly increased tissue uptake of doxorubicin in bladder, diaphragm and abdominal wall during the first 10 min of i.p. administration. These findings may have significance in the design of improved strategies to increase tissue concentrations of chemotherapy delivered by an i.p. route.

Abdomen↗

Pharmacokinetics and tissue distribution of recombinant human alpha A, D, A/D(Bgl), and I interferons and mouse alpha-interferon in mice.

The pharmacokinetics and tissue distribution in mice of several recombinant human alpha-interferons [rHuIFN-alpha A, D, I, and A/D(Bgl)] as well as natural mouse alpha-interferon (MuIFN-alpha) were assessed following single intravenous injections. The serum profiles of rHuIFN-alpha A, rHuIFN-alpha D, rHuIFN-alpha A/D(Bgl), and MuIFN-alpha were similar, whereas those following rHuIFN-alpha I showed a much longer terminal elimination phase. Differences in elimination half-life, volume of distribution, and total body clearance between these IFNs were observed. There was appreciable uptake of IFN in the kidney: the amount of each interferon per gram of tissue in the kidney ranges from 1 to 9 times the amount found in the serum. The greatest uptake appeared with rHuIFN-alpha D, followed by rHuIFN-alpha A, rHuIFN-alpha A/D(Bgl), and MuIFN-alpha. The only exception was rHuIFN-alpha I which showed no uptake into the kidney.

Animals↗

Disposition of 8-methoxypsoralen in the rat: methodology for measurement, dose-dependent pharmacokinetics, tissue distribution and identification of metabolites.

The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after a single i.v. dose. Blood samples were collected serially and analyzed using a sensitive and specific assay for [14C]-8-MOP. Total body clearance of 8-MOP was 7.3, 3.9, 1.7, 1.0, 0.78 and 0.42 liters/kg/hr at doses of 0.2, 1.0, 2.5, 5.0, 10 and 20 mg/kg, respectively. The decline in total body clearance indicates that elimination of 8-MOP is dose-dependent in the rat. After i.v. administration of 10 mg/kg of 8-MOP, 71 and 26% of the dose was recovered within 72 hr in the urine and feces, respectively. Unchanged 8-MOP accounted for less than 1% of the excreted radioactivity. In tissue distribution studies at 0.5, 2 and 5 hr after i.v. administration, 8-MOP distributed rapidly to all tissues and concentrated in the fat and kidneys. The concentration of 8-MOP in the skin was 0.4 to 0.6 times that in the blood. Eleven metabolites of 8-MOP were detected in the urine. The metabolites identified after enzymatic hydrolysis were 8-hydroxypsoralen; 5-hydroxy-8-methoxypsoralen; 5,8-dihydroxypsoralen; 5,8-dioxopsoralen; 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid and 8-MOP (formed by ring closure of a coumaric acid metabolite). Thus, these studies indicate that 8-MOP is metabolized in the rat by 1) O-demethylation; 2) hydroxylation at position 5; 3) hydrolysis of the lactone ring and 4) oxidation of the furan ring, a pathway already confirmed in insects, dogs and humans.

Animals↗

The tissue distribution and the pattern of excretion of [14C]-13-labeled 12, 13-epoxytrichothec-9-ene in mice and rats.

The distribution in the mouse tissues of 13-[14C]-12,13-epoxtrichothec-9-ene administered intravenously was determined by whole-body autoradiography and by tracing the radioactivity of the tissues oxidized in an Auto Sample Oxidizer. The appearance of the label in urine and feces was also followed by the tracer technique. The distributions of radioactivity in tissues as determined by the two methods were almost identical. On the autoradiograms of mice killed 10 min after the injection, marked blackening of the film was observed at the sites corresponding to the liver, kidney, and bladder with urine, and much less darkening at other sites. The radioactivities contained in the liver, kidney, urine and small intestine were 13.3, 2.3, 2.6 and 10.2% of the dose, respectively. The labeled toxin was rapidly excreted into urine and feces, 56.0 and 4.9% in 6 hr and 66.7 and 28.0% in 24 hr after injection, respectively. Oral administration of the labeled toxin to mother mice resulted in the appearance of radioactivity in the stomach contents of 7-day suckling mice, thus demonstrating indirectly the secretion of the toxin into the milk. An attempt to show a respiratory route of excretion in rats given the radioactive compound orally or intravenously failed to detect any radioactivity in the expired CO2 collected for 6 hr, suggesting that the 14C in the epoxy ring was intact.

Animals↗

Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys.

Ribavirin has been shown to have broad-spectrum antiviral. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 microCi of [14C]ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected [14C]ribavirin was detected in expired CO2. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats.

Animals↗

Tissue distribution of the tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and its metabolites in F344 rats.

The tissue distribution of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the F344 rat was studied by whole-body autoradiography and high-performance liquid chromatography. The results of the wholebody autoradiography experiments indicate that the substance is able to freely cross biological membranes and reach all tissues of the body. A high level of tissue-bound metabolites occurred in the mucosa of the ethmoturbinates, in the lung, and the liver, which are the targets for the carcinogenicity of NNK in F344 rats. However, tissue-bound radioactivity was also present in non-target tissues such as the lateral nasal gland(Steno's gland), the tracheal mucosa, and the mucosa of the nasopharyngeal duct. A high level of unbound radioactivity occurred in the preputial gland, submaxillary and adrenal glands, and the urinary and gastrointestinal systems. High localization of unbound radioactivity was observed in the stomach lumen not only after p.o. but also after i.v. administration of NNK. Analysis of extracts of the stomach contents by high-performance liquid chromatography indicated that, due to their basicity, NNK and its metabolites were trapped in the gastric juice and later reabsorbed from the intestinal tract. Analysis of unbound metabolites in various tissues and in the urine after i.v. or p.o. administration of [carbonyl-14C]NNK indicated metabolism and excretion of products resulting from alpha-carbon hydroxylation, carbonyl reduction, and pyridine N-oxidation of NNK. After p.o. administration of [14CH3]NNK, 47% of the dose was recovered as 14CO2. [carbonyl-14C]NNK, however, was not metabolized to 14CO2. Levels of in vitro metabolism of [14CH3]-NNK to 14CO2 or incorporation of radioactivity into the acid-insoluble material after incubation with [carbonyl-14C]NNK were the highest in the nasal mucosa. Thus, the high activity of NNK-activating enzymes present in the nasal cavity is apparently an important factor in the etiology of NNK-induced neuroepitheliomas. In vitro autoradiography experiments showed that NNK is metabolized in the mucosa of the ethmoturbinates, the lung, and the liver, suggesting that the tumors are induced by metabolites formed locally in the target tissues. In the lung, the labeling was higher in the bronchial tree than in the lung parenchyma.

Animals↗

Different tissue distributions of two types of thiol proteinase inhibitors from rat liver and epidermis.

The concentrations of two types of endogenous inhibitors of thiol proteinases were determined in soluble extracts of various rat tissues by means of a sensitive enzyme immunoassay method, which consisted of solid-phase immobilized anti-rat liver inhibitor or anti-rat epidermal inhibitor and antibodies labeled with horseradish peroxidase. The minimum detectable amounts of inhibitors from liver and epidermis were 30 pg and 3 pg/assay, respectively. The tissue distributions of the epidermal and liver-type inhibitors were found to differ. The liver-type inhibitor was found to be widely distributed in various tissues at levels of 76-420 ng/mg protein, whereas the epidermal-type inhibitor was found at high levels in the skin, tongue, esophagus, stomach, intestine, and vagina, but at quite low levels in other tissues tested.

Animals↗

The disposition, tissue distribution, and cellular transport of N-[[(trimethylamino)boryl]carbonyl]-L-phenylalanine methyl ester in CF1 mice.

The disposition and tissue distribution of 14C-labeled N-[[(trimethylamino)boryl]carbonyl]-L-phenylalanine methyl esther (1) determined in CF1 mice following i.v., p.o., and i.p. administration. Compound 1 was found to undergo rapid and extensive metabolism, and the majority of the radioactivity was found in the skin and carcass regardless of the route of administration. Approximately 55% of the radioactivity was recovered in urine and feces after 78 h; however, excretion via these routes was not complete. Degradation of compound 1 occurred at the amide bond at low pH (0.8) but at the ester bond a physiological pH. This difference in degradation was reflected in elevation of the blood radioactivity levels after p.o. administration compared to i.p. and i.v. administration.

Administration, Oral↗

Cloning and tissue distribution of the human B3GALT7 gene, a member of the beta1,3-Glycosyltransferase family.

We report here the cloning and tissue distribution of the human B3GALT7 gene, a member of the beta1,3-Glycosyltransferase family, structurally related to the beta1,3-Galactosyltransferase family and beta1,3- N -acetylglucosaminyltransferase family, isolated from a human lung cDNA library. B3GALT7 is mapped to chromosome 19q13.2 by browsing the UCSC genomic database. It contains an ORF with length of 1191bp, encoding a protein with a signal peptide sequence and galactosyl-T domain, and its molecular weight and isoelectric point is predicted to be 43.3 kDa and 8.67 respectively. The molecular weight of the protein when expressed in E. coli corresponded to that expected. Northern blotting showed that B3GALT7 was highly expressed in lung, throat and ileum, whereas the expression level was low in tongue, breast, uteri, testis. In addition, it was also demonstrated that B3GALT7 is differentially transcribed in human tumor cell lines.

Amino Acid Sequence↗

Effects of mucosal metallothionein in small intestine on tissue distribution of cadmium after oral administration of cadmium compounds.

The effect of mucosal metallothionein (MT) preinduced by zinc (Zn) on tissue distribution of cadmium (Cd) after administration of Cd with several chelating agents was studied in rats. After Cd-cysteine (Cd-Cys) was incubated with intestinal Zn-MT in vitro, all the Cd dissociated from Cys and exchanged the Zn bound to MT. However, dissociation of Cd bound to EDTA (Cd-EDTA) was not observed in the incubation mixture containing intestinal Zn-MT. The concentration of Cd in intestinal mucosa reached a maximum 16 hr after oral administration of Cd-Cys. The Cd level in the intestine was higher than that in the liver and kidney and was similar to that occurring after oral administration of CdCl2. The amount of Cd distributed to the liver and kidney after Cd-EDTA administration was about 30% of the level after CdCl2 administration. Even at 15 mg Cd/kg Cd-EDTA, the Cd level in the intestinal mucosa reached a plateau after 2-4 hr, as it did in the liver and kidney. When Cd-Cys was administered po to control or to Zn-pretreated rats, it was found that Zn pretreatment increased the concentration of Cd in the kidney, as was the case after oral administration of CdCl2. This effect of Zn pretreatment was not observed after oral administration of Cd-EDTA. When Cd-MT was injected into the duodenum, the intestinal absorption of Cd was 60% of that after CdCl2 administration. After the duodenal administration of Cd-MT, at all doses, the concentration of Cd in the kidney was higher than that in the liver. These results suggest that mucosal MT in the small intestine might trap Cd absorbed from the intestinal lumen and transport it to the kidney.

Administration, Oral↗

Tissue distribution of moxaverine-hydrochloride in the rabbit eye and plasma.

OBJECTIVE: The aim of this study was to determine the tissue distribution and epithelial penetration of moxaverine-hydrochloride (MOX) in the rabbit eye. METHODS: For systemic application, a radioactively labeled MOX solution was injected into the ear vein of Dutch-belted pigmented male rabbits. For topical dosing, an identical solution was administered. At predetermined time points, rabbits were sacrificed, the eyes dissected, and the amount of MOX in the ocular tissues measured. To examine the MOX permeability across the corneal epithelium, transport studies using rabbit corneal epithelial cell culture were conducted and the respective apparent permeability coefficient in absorptive (a to b) or secretive (b to a) direction was calculated. RESULTS: Topical delivery resulted in high concentrations of MOX in the cornea and conjunctiva, although other tissues of the anterior part yielded lower MOX concentrations. In the tissues of the posterior part, high amounts were detected in the retina. Plasma levels were low. The apparent permeability coefficient across corneal epithelial cell layers was in the range of 10(5) cm/s, exhibiting no apparent directionality. CONCLUSION: A topical dosing of MOX to posterior regions of the eye seems feasible. MOX levels in the posterior part of the eye were remarkably high, without causing stringent plasma levels. The high apparent permeability coefficient of MOX across the corneal epithelial cell layers might be caused by the lipophilic nature of the drug and was in the range of other compounds with comparable physicochemical properties.

Animals↗

Endocrine-metabolic pattern and adipose tissue distribution.

The associations between cardiovascular disease (CVD), non-insulin-dependent diabetes mellitus (NIDDM) and abdominal fat distribution are well established. The most important adipose tissue depot in this context is probably the mass of intra-abdominal adipose tissue which has been found to be associated with CVD, NIDDM and their established metabolic risk factors. This type of adipose tissue distribution is also associated with multiple endocrine aberrations, probably comprising an increased responsiveness of the hypothalamo-adrenal axis and a parallel or secondary decreased activity of the hypothalamic-gonadal axis. Epidemiological studies in both men and women indicate that this may be a consequence of psychological stress. Recently, indirect evidence for decreased production of growth hormone in this condition has also been recognized. These multiple and interrelated abnormalities comprise a syndrome where the primary disturbance could be localized to the hypothalamus and the main peripheral consequences would be metabolic effects on the mass and function of intra-abdominal adipose tissue. This in turn, probably by the effects of elevated concentrations of portal free fatty acid levels on the liver, could result in insulin resistance and other metabolic risk factors known to be strongly associated with CVD and NIDDM.

Abdomen↗

Tissue distribution of atrial natriuretic factor in normal and pathologic human hearts.

The tissue distribution and possible neuroendocrine nature of atrial natriuretic factor (ANF) were studied, using the avidin-biotin-peroxidase technique and antibodies to ANF, chromogranin (Ch), and neuron-specific enolase (NSE). Tissues examined included: Group 1, formalin-fixed and fresh frozen atrial tissue from adjacent areas of the hearts from two heart-lung-transplant patients; Group 2, the entire atria and sampling of other areas from formalin-fixed hearts of five gunshot wound or automobile accident victims; and Group 3, formalin-fixed right auricular tissue from 19 open-heart-surgery patients. In each case of Group 3, the ANF score, expressed as the product of the percentage of stained areas by the staining intensity, was correlated with age, weight, height, blood pressure, ejection fraction, and degree of coronary arterial stenosis. It was found that: (a) ANF was limited to atrial myocytes; the staining was significantly stronger in the right atrium, diffuse and most intense in auricles and pectinate muscles, diffuse and strong in subendocardium, focal and weak in other areas; (b) although ANF has been reported to be a peptide hormone stored in dense-core granules, it does not seem to belong to the diffuse neuroendocrine system because Ch and NSE were consistently absent in cardiac myocytes; and (c) although the limited numbers of evaluable clinical parameters do not significantly correlate with ANF scores, a change in the pattern and intensity of ANF staining was noted in some cases of Group 3.

Adult↗

Nucleotide sequence and tissue distribution of three insulin-like growth factor I prohormones in salmon.

Tissue distribution and potential alternative splicing of insulin-like growth factor I (IGF-I) messenger RNA were studied using reverse transcriptase-polymerase chain reaction (RT-PCR) on RNA from several tissues at various stages of the life cycle of coho salmon (Oncorhynchus kisutch). DNA sequence analysis of RT-PCR products revealed three IGF-I mRNA transcripts, designated Ea-1, Ea-2, and Ea-3, which code for three distinct prohormones, IGF-IA-1, IGF-IA-2, and IGF-IA-3, respectively. The E-domain of proIGF-IA-1 is 35 amino acids long and shares 77% sequence identity with the E-domain of human proIGF-IA, which is also 35 amino acids long. The proIGF-IA-2 and proIGF-IA-3 E-domains are homologous to the proIGF-IA-1 E-domain but contain 27 and 39 amino acid inserts, respectively, between Lys86 and Glu87. In the human IGF-I gene Lys86 is coded by exon 4 and Glu87 is coded by exon 6. This suggests that Ea-2 and Ea-3 transcripts may be the result of alternative splicing during pre-mRNA processing. All three transcripts were readily detectable using a solution hybridization/RNase protection assay. Furthermore, RT-PCR and DNA sequencing analysis indicate the presence of three IGF-I prohormones in another member of the Salmonidae family, the Atlantic salmon (Salmo salar). An analysis of IGF-I and -II E-domains from several vertebrates suggests that certain chemical and physical properties of the molecule are well conserved despite wide variations in primary structure. Ea-1, Ea-2, and Ea-3 transcripts were found in whole embryos, and liver, muscle, and brain of juvenile and adult salmon. At least one IGF-I transcript was found in heart, kidney, testes, ovary, adipose tissue, and spleen of juvenile salmon. These results indicate that IGF-I is expressed during embryonic development of fish, and that most tissues are capable of IGF-I mRNA production. These data also indicate that pre-mRNA transcripts can be alternatively spliced to yield at least three prohormones.

Alternative Splicing↗

Pharmacokinetics and tissue distribution of SB-251353, a novel human CXC chemokine, after intravenous administration to mice.

The pharmacokinetics and tissue distribution of SB-251353, a novel truncated form of the human CXC chemokine growth-related gene product beta, were studied after intravenous administration to the mouse (0.1--250 mg/kg). At the lowest dose, the clearance exceeded blood flow to the kidney. As the dose increased, clearance approached the glomerular filtration rate in the mouse. Clearance of this chemokine may be mediated by its pharmacologic receptor, CXCR2, via endocytosis with subsequent lysosomal degradation, as has been observed for several growth and hematopoietic factors. Apparent distribution volumes were high (> or =1 l/kg). Moderate binding to the Duffy antigen/receptor for chemokines on erythrocytes was observed. Consistent with the pharmacokinetic analysis, microscopic autoradiography showed uptake into renal proximal tubule epithelial cells. Limited excretion of SB-251353 in the urine (<2%) was consistent with catabolism of the chemokine in the tubules. Binding to hepatic sinusoids and connective tissue in the dermis was observed. This possibly reflected interaction of SB-251353 with heparin sulfate proteoglycan and may explain the large distribution volumes. This first study of the disposition of a chemokine provides insight into mechanism of action and physiological factors that may influence chemokine pharmacodynamics.

Animals↗