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At least 19 recordsLinked to original sources
PubMed1986

Effects of sera from Cohen, genetically determined diabetic rats, streptozotocin diabetic rats and sucrose fed rats on in vitro development of early somite rat embryos.

The effects of sera from genetically determined Cohen diabetic rats, streptozotocin (STZ) diabetic rats and non-diabetic control rats fed a 72% sucrose diet on the in vitro development of 9 1/2 day old rat embryos from control rats have been studied. Hyperglycemic sera from diabetic rats had a high teratogenic effect: abnormalities were seen in 41.5% of embryos cultured in serum from Cohen diabetic animals and in 54% of embryos cultured in serum from STZ-diabetic rats. Malformations were seen in 25-27% of embryos cultured in serum from 2 groups of control rats fed a high sucrose diet compared with 10.7% in serum from control rats maintained on regular diet. When embryos from the experimental groups were cultured in serum from control rats on regular diet malformations were seen in 24.7% of embryos from Cohen genetically determined diabetic rats vs 10.9-12.4% in embryos from 2 non-diabetic groups. Only 14% of embryos from STZ-diabetic rats exhibited malformations when cultured in the control serum, but 42% of embryos from the same rats showed abnormalities when grown in serum from STZ-diabetic rats. Normalization of glucose level in the serum of STZ-diabetic rats by prior injection of insulin did not reduce the high incidence of malformations (51%). The high rate of embryonic malformations correlated with the ultrastructural changes of their visceral yolk sac endoderm. We suggest that serum from diabetic rats is teratogenic even at moderate hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Reduced urinary noradrenaline excretion during rest, exercise and cold stress in trained rats: a comparison between physically-trained rats, cold-acclimated rats and warm-acclimated rats.

Physically trained rats were compared with cold-acclimated rats. Trained as well as cold-acclimated rats showed cardiac and adrenal hypertrophy. Cardiac noradrenaline (NA) content was increased in both groups of rats but only the trained rats had an increased cardiac NA concentration. The adrenal NA content was increased in both groups but only the trained rats had an increased adrenal content of adrenaline (A). The spleen of trained rats had an increased NA content, while that of cold-acclimated rats had a decreased NA content. The submandibular glands of cold-acclimated rats were enlarged and had an increased NA content. Trained as well as cold-acclimated rats had lower urinary NA excretions during rest, after exercise and during cold stress when compared with controls. However, only the trained rats had a reduced net increment in NA excretion after exercise, whereas there was no difference between the increments of cold-acclimated and control rats. Six months after cessation of training, ex-trained rats still had an increased heart ratio and a reduced urinary NA excretion after exercise. It is suggested that physical training induces "cross tolerance" to cold stress, while cold-acclimation does not lead to "cross tolerance" to acute exercise.

Acclimatization↗
PubMed1991

The Interleukin-6-dependent DNA-binding protein gene (transcription factor 5: TCF5) maps to human chromosome 20 and rat chromosome 3, the IL6 receptor locus (IL6R) to human chromosome 1 and rat chromosome 2, and the rat IL6 gene to rat chromosome 4.

Using two panels of somatic cell hybrids segregating either human or rat chromosomes, the gene encoding the interleukin-6-dependent DNA-binding protein, also called liver activator protein (designated transcription factor 5: TCF5), was assigned to human chromosome 20 and to rat chromosome 3. The TCF5 gene might be identical with the NF-IL6 gene. The locus encoding the IL6 receptor gene (IL6R) was localized to human chromosome 1 and rat chromosome 2. An IL6R-like (IL6RL) locus was also assigned to human chromosome 9. In addition, the rat interleukin-6 (IL6) gene was assigned to rat chromosome 4. These mapping data allow one to extend comparison between the rat, mouse, and human gene maps.

Animals↗
PubMed1990

Delayed postnatal behavioral development in spontaneously epileptic rats and tremor rats, and poor operant performance in spontaneously epileptic rats.

Postnatal behavioral development and learning ability of operant performance were examined in spontaneously epileptic rats (SER: zi/zi, tm/tm), and the original tremorous mutant strains of rats, tremor rats (tm/tm) and zitter rats (zi/zi) and their controls. Before the eyes opened, the increase in body weight and the age of achieving the righting reflex on a surface were no significantly different between the SER and their littermates without epileptic seizures (SER-N: zi/zi, tm/+ or zi/zi, +/+), and between tremor rats and the original strain Kyo: Wistar rats. After the eyes opened, the increase in body weight, age of achieving the righting reflex in air and traction performance, and the development of rotarod performance, were delayed in SER and tremor rats in comparison with other groups of rats. The zitter rats were apparently inferior in their development of rotarod performance in comparison with the same zitter homozygous SER-N. Operant performance was more inferior in SER than in SER-N and in tremor rats than in Kyo: Wistar rats. The differences were much more marked between SER and SER-N than between tremor and Kyo: Wistar rats. Thus, homologous tm genes and the coexistence of homologous tm and zi genes have an inhibitory effect on postnatal behavioral development and learning ability.

Animals↗
PubMed1977

Action of rat prolactin on plasma somatomedin levels in the rat and on somatomedin release from perfused rat liver.

Rat prolactin at a concentration of 50 ng/ml perfusion medium stimulated the production of somatomedin-like activity (SLA) from the perfused liver of normal rats. The effect was demonstrable in perfusions performed at 11.00 h in which rat prolactin caused a mean (+/- S.E.M.) increase in the uptake of [35S]sulphate into rat costal cartilage in vitro of 64 +/- 14% in comparison with controls, but at 15.00 h no effect was observed. No effect or rat prolactin on hypophysectomized rat liver was detectable at 11.00 h. Hypophysectomized and sham-operated rats were given five intravenous injections of 50 microgram rat prolactin or a similar volume of hormone solvent at 12 h intervals. Plasma somatomedin activity (SMA) and cartilage metabolism, measured by the uptake of radioactive sulphate and thymidine by costal cartilage in vitro, were similar in hypophysectomized animals given rat prolactin or hormone solvent. Sham-operated rats given rat prolactin showed a significant increase of plasma SMA and cartilage metabolism compared with control animals. The production of SLA by rat liver in response to rat prolactin may be related to the density of specific hepatic lactogenic receptors, since these are absent or present only in low numbers in hypophysectomized animals.

Animals↗
PubMed1989

Genetic studies in inbred BB/Wor rats. Analysis of progeny produced by crossing lymphopenic diabetes-prone rats with nonlymphopenic diabetic rats.

BB/Wor diabetes-prone (DP) rats are lymphopenic and frequently develop insulin-dependent diabetes. Diabetes-resistant (DR) BB/Wor rats are not lymphopenic and become diabetic rarely and at a significantly younger age. To examine the genetic basis for diabetes, lymphopenia, and age at onset of diabetes among inbred BB/Wor rats, we crossed nonlymphopenic diabetic rats with lymphopenic DP animals and studied F1, F2, and backcross progeny. F1 rats were neither diabetic nor lymphopenic. Diabetes (both types) and lymphopenia reappeared among F2 rats, confirming the permissive association of diabetes and lymphopenia and the recessive nature of both. The absence of diabetes in F1 rats also suggested that the combination of genes responsible for diabetes among lymphopenic and nonlymphopenic rats may be distinct. Nonlymphopenic parental, F1, and F2 rats revealed normal lymphocyte subsets, including CD8+ and RT6+ T-lymphocytes. Lymphopenic parental and F2 rats revealed the absence of CD8+ and RT6+ cells, indicating that these T-lymphocyte abnormalities of lymphopenic DP rats segregate with the lymphopenia gene. The distribution of the ages at onset of diabetes among F2 lymphopenic and F2 intercross rats was significantly earlier than among lymphopenic parental and backcross animals, suggesting that the age of diabetes onset is a heritable trait and that the gene(s) or genetic modifier(s) responsible for the earlier onset of F2 diabetes was acquired from the nonlymphopenic parents. Our genetic studies also confirmed the observations that the 2- and 7-kilobase Bam HI fragments of the MHC class I region do not correlate with diabetes or lymphopenia.

Age Factors↗
PubMed1976

The hypothalamic-neurohypophysial system of the rat: localization and quantitation of neurophysin by light microscopic immunocytochemistry in normal rats and in Brattleboro rats deficient in vasopressin and a neurophysin.

The cellular distribution of neurophysin was examined in hypothalami and neural lobes of normal Long-Evans rats and Brattleboro rats deficient in vasopressin and a major neurophysin. Tissue sections were treated with antisera to bovine, human, and rat neurophysins, using immunoperoxidase bridge techniques. Antisera to oxytocin (OT) and vasopressin (VP) were applied to adjacent sections. Two distinct cell populations were discernible in both magnocellular nuclei on the basis of the intensity of cytoplasmic staining. About half of the magnocellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of homozygous Brattleboro rats with diabetes insipidus (DI) were devoid of immunoreactive neurophysin, OT, and VP. These cells were presumably the defective counterparts of those neurons that produce VP and its associated neurophysin in normal and heterozygous Brattleboro rats. The cells in homozygous DI rats which were stained with immunoreaction products to NP and OT were more concentrated in the dorsal part of the SON and in the periphery of the PVN. Spatial segregation of different neurons was also seen in the neural lobe, where clusters of stained axons were surrounded by bundles of nerve fibers lacking immunoreactive material. In normal rats and heterozygotes nearly all magnocellular neurons reacted immunologically with antiserum to neurophysin but with different intensities, so that "dark" and "light" cells could be distinguished. The darker cells in heterozygous Brattleboro rats had the same pattern of distribution as cells which contained OT. In homozygous DI rats, only some of those cells which contained neurophysin and OT exhibited a positive reaction with antiserum to VP due to slight reactivity with OT. The results obtained in the homozygous Brattleboro rat would suggest that OT and VP and their associated neurophysins are produced in different neurons in both the SON and PVN. However, in normal rats and in heterozygous Brattleboro rats, VP appeared to be present in both OT-positive and OT-negative neurons suggesting that some cells may have the capacity to synthesize two hormones.

Animals↗
PubMedDate not supplied

Inhibitory action of rat insulin and synthetic rat C-peptide on insulin secretion in the perfused rat pancreas.

In order to determine whether both insulin and C-peptide have an inhibitory action on insulin secretion, the isolated rat pancreas was perfused with exogenous rat insulin or synthetic rat C-peptide in the presence of high or low concentration of glucose. In the presence of 2.8 mM glucose, exogenous rat insulin (4 or 10 ng/ml) and C-peptide 1 and 2 (100 ng/ml) show no effect on the insulin levels in the outflow from the perfused pancreas. However, the insulin response to 16.7 mM glucose decreased in the presence of exogenous rat insulin or synthetic rat C-peptide, showing a biphasic pattern of glucose-induced insulin release. When rat insulin or C-peptide were added at 20 min and removed at 40 min while the isolated pancreas was exposed to a 60-min glucose infusion (16.7 mM), glucose-induced insulin secretion decreased during the infusion of rat insulin or C-peptide. The present study clearly showed that exogenous rat insulin and synthetic rat C-peptide 1 and 2 inhibited glucose-induced insulin secretion. Although the suppressive mechanisms of the exogenous insulin and the C-peptide on insulin release are not yet proved, the inhibitory process is considered to be related to cyclic AMP in the pancreatic B-cell.

Animals↗
PubMed1992

Experimental Yersinia enterocolitica infection in rats: analysis of the immune response to plasmid-encoded antigens of arthritis-susceptible Lewis rats and arthritis-resistant Fischer rats.

Recently, experimentally Yersinia-induced arthritis in Lewis and SHR rats has been described as a potential animal model for analyzing the pathomechanism of reactive arthritis (Toivanen et al. 1986; Hill and Yu 1987). We could confirm that Lewis but not Fischer rats develop aseptic arthritis about 2 weeks after an intravenous inoculation of Yersinia enterocolitica, serotype 0:8 (Hill and Yu 1987). Moreover, we compared the antibody response to virulence-associated Yersinia antigens (Yops) of experimentally infected Lewis rats with that of Fischer rats using an enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The ELISA results revealed a more rapid and vigorous specific IgG, IgA and IgM response for Lewis rats than for Fischer rats in the early state of infection. As demonstrated by immunoblotting, the IgG response was directed predominantly against the plasmid-encoded YopM, YopH, YopD and the V-antigen during the acute phase followed by antibodies against YopE and YadA. Although both rat strains seroconverted against this set of antigens, IgG antibodies to YadA were more prevalent and of higher titer in arthritis-susceptible rats compared to arthritis-resistant rats.

Animals↗
PubMed1971

Aortic reactivity and electrophysiology in normotensive rats, spontaneously hypertensive rats and rats made hypertensive with desoxycorticosterone plus salt.

The mechanical and electrophysiological activity of rings and strips of thoracic aortic smooth muscle taken from normotensive, DOCA-hypertensive and New Zealand spontaneously hypertensive (A.S. strain) rats have been compared. Aortae from A.S.-hypertensive rats developed less tension in the presence of noradrenaline and K+ than those isolated from normotensive and DOCA-hypertensive rats. Aortae from DOCA-hypertensive rats developed the same tension in response to K+ as normotensive rats but were less reactive to noradrenaline. Measurements of resting membrane potentials from the three groups of rats demonstrated that whereas normotensive and DOCA-hypertensive rats had similar resting membrane potentials, those from A.S.-hypertensive rats were significantly lower (P<0.001). It is suggested that the enhanced responsiveness of intact vascular beds in A.S.-hypertensive rats is a consequence of a change in the geometry of the blood vessels rather than an increase in the contractor response of the smooth muscle cells.

Animals↗
PubMedDate not supplied

Effects of rat interleukin-2 and rat interferon on the natural killer cell activity of rat spleen cells after thermal injury.

The natural killer cell activity of splenocytes from rats with scald injury was observed to be significantly suppressed at 7 days after injury compared with that of normal nonburned controls. Incubation of splenocytes from normal rats or rats with burn injury with either rat interleukin-2 or rat interferon (IFN-alpha and IFN-beta) significantly increased the natural killer cell activity. Addition of a rabbit anti-rat interferon antibody to spleen cells incubated with interleukin-2 did not produce any significant alteration in interleukin-2-related enhancement of natural killer cell activity. These results suggest that enhancement of natural killer cell activity after incubation of splenocytes with interleukin-2 is not due to interferon production but is an independent event. Preincubation of spleen cells with a mouse monoclonal antibody to rat interleukin-2 receptor was observed to abolish the interleukin-2-related enhancement of natural killer cell activity completely, whereas it partially blocked the interferon-related enhancement. These results were also confirmed by enhancement of natural killer cell activity of burned rats after in vivo administration of interleukin-2. Our studies thus indicate that after thermal injury, the observed decrease of natural killer cell activity can be enhanced by both interleukin-2 and interferon independently of each other. The decreased natural killer cell activity may be due to a decrease in interleukin-2 production or availability and not to an interleukin-2 receptor defect. These studies thus point toward a potential therapeutic significance of interleukin-2 in enhancing immune function after thermal injury.

Animals↗
PubMed1992

Rat thymic epithelium positively selects mouse T cells with specificity for rat MHC class II antigens but fails to induce detectable tolerance in the mouse T cells to the rat MHC antigens.

BALB/c (H-2d) nude mice were grafted with allogeneic AKR/J (H-2k) or xenogeneic (ACI-N rat, RT1av1) fetal thymuses which were depleted of hemopoietic cells by incubating with 2'-deoxyguanosine (2'dGuo) in vitro prior to grafting. The nylon-wool-passed LN T cells from nude mice grafted with 2'dGuo-treated AKR/J thymus showed a poor proliferative response to B10BR (H-2k) stimulator cells, confirming that mouse thymic epithelium has the capacity to induce tolerance against the mouse MHC antigens on the thymic epithelium. On the other hand, the nylon-wool-passed LN T cells from nude mice grafted with untreated or 2'dGuo-treated ACI/N rat thymus showed significant proliferative responses to ACI/N, which can be blocked by anti-rat MHC class II mAb, whereas the nylon-wool-passed LN T cells from nude mice grafted with syngeneic thymus hardly responded to the xenogeneic stimulator cells. These results suggest that rat thymic stromal cells including thymic epithelium can not induce detectable tolerance in mouse T cells to rat MHC antigens; but rat thymic epithelium may positively select mouse T cells with specificity for rat MHC class II antigens, resulting in a mouse T cell repertoire with strong xeno-reactivity.

Animals↗
PubMed1985

Effects of 5-hydroxytryptamine uptake blockers on the concentration in brain of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in male rats, pro-oestrous rats and ovariectomized rats treated with oestrogen and progesterone.

The aim of this study was to determine the effect of 5-hydroxytryptamine (5-HT) uptake blockade on 5-HT turnover by measuring the concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in brain with the aid of high performance liquid chromatography and electrochemical detection. The indoleamines were measured in the anterior hypothalamus (AH), posterior hypothalamus (PH) and raphe nuclei 30 min after the i.v. injection of either alaproclate (30 mg/kg) or zimelidine (20 mg/kg). The effect of alaproclate was studied in male rats, pro-oestrous female rats, rats ovariectomized and injected s.c. with 20 micrograms oestradiol benzoate (OB) on dioestrus and at 12.00 h of the next day (presumptive pro-oestrus) with 2 mg progesterone (model 1) and rats ovariectomized 3-4 weeks before an s.c. injection of 20 micrograms OB followed 72 h later by an s.c. injection of 2 mg progesterone (model 2). Alaproclate caused a significant decrease in the 5-HIAA/5-HT ratio in the AH and PH of the brain of male rats, in the PH and raphe nuclei in pro-oestrous rats and model 1, and in the raphe nuclei alone in model 2. Zimelidine had no effect on the 5-HIAA/5-HT ratio in any area in model 2. In male rats the injection of parachlorophenylalanine produced a marked reduction in the brain concentrations of 5-HT and 5-HIAA, but the 5-HIAA/5-HT ratio was unchanged by a subsequent injection of alaproclate. None of the pharmacological agents affected significantly the brain concentrations of noradrenaline, dopamine or dihydroxyphenylacetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1991

Long-term effect of a sheep antiserum to rat growth hormone in vivo in rats is explained by the rat anti-sheep immunoglobulin response.

A specific antiserum to rat GH (anti-rGH) raised in sheep was used in young male and lactating rats. In both models a group of rats was found which appeared to generate a low response (low responders) to the injected sheep immunoglobulin, and was characterized by the ability of the antiserum to cause inhibition of growth for more than 21 days in the male rats, and to abolish milk yield when prolactin concentrations were lowered in the females. In the groups which generated a high response to the anti-rGH (high responders), growth was retarded for only 2-3 days in male rats, with a moderate milk yield maintained in lactating animals. The low-response animals were found to have a significantly longer half-life for circulating anti-rGH, when compared with the high-response animals. After 21 days, in the age-matched male rats, levels of anti-rGH were undetectable in the high-responders, whereas the low-response animals, which were nearly 160 g lighter, still had approximately 4.5 ml anti-rGH/l in their circulation. This anti-rGH was still capable of neutralizing GH, as concentrations of insulin-like growth factor-I (IGF-I) were 13.6 +/- 3.5 (mean +/- S.E.M.) and 76.9 +/- 2.0 nmol/l in the low-response and high-response groups respectively. The reason for these differences would appear to be that the immune response mounted by these low-response animals to the exogenous sheep immunoglobulin (i.e. rat anti-sheep) 7 days after treatment was less than 10% of that seen in the high-response group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The effects of an antibody to the rat transferrin receptor and of rat serum albumin on the uptake of diferric transferrin by rat hepatocytes.

The role of high-affinity specific transferrin receptors and low-affinity, non-saturable processes in the uptake of transferrin and iron by hepatocytes was investigated using fetal and adult rat hepatocytes in primary monolayer culture, rat transferrin, rat serum albumin and a rabbit anti-rat transferrin receptor antibody. The intracellular uptake of transferrin and iron occurred by saturable and non-saturable mechanisms. Treatment of the cells with the antibody almost completely eliminated the saturable uptake of iron but had little effect on the non-saturable process. Addition of albumin to the incubation medium reduced the endocytosis of transferrin by the cells but had no significant effect on the intracellular accumulation of iron. The maximum effect of rat serum albumin was observed at concentrations of 3 mg/ml and above. At a low incubation concentration of transferrin (0.5 microM), the presence of both rat albumin and the antibody decreased the rate of iron uptake by the cells to about 15% of the value found in their absence, but to only 40% when the diferric transferrin concentration was 5 microM. These results confirm that the uptake of transferrin-bound iron by both fetal and adult rat hepatocytes in culture occurs by a specific, receptor-mediated process and a low-affinity, non-saturable process. The low-affinity process increases in relative importance as the iron-transferrin concentration is raised.

Animals↗
PubMed1976

Metabolism of a benzothiazine compound (SQ 11,579) by the intact rat, isolated perfused rat liver, and rat-liver microsomes.

1. The metabolic dispositions of a benzothiazine compound (SQ 11,579) by the intact rat, isolated perfused rat liver, and rat-liver microsomes have been investigated, and the results compared. 2. The drug was well absorbed after oral administration to rats and was widely distributed in all tissues, which, with the exception of brain, had higher concentrations of the drug, its metabolites, or both, than did plasma. 3. Metabolism by rat-liver microsomes included N-oxidation, N-demethylation, S-oxidation and aryl hydroxylation. Metabolites hydroxylated in the aromatic ring were excreted only in bile, both by the isolated perfused rat livers and by anaesthetized bile-duct-cannulated rats. 4. Liver perfusion of the benzothiazine or its monodesmethyl analogue (V) resulted in temporary cessation of the flow of perfusate through the organ. The benzothiazine sulphoxide (IV) had only a slight effect on the flow of liver perfusate, but IV followed by I caused the flow of perfusate to cease.

Administration, Oral↗
PubMed1989

Metabolism of triiodothyroacetic acid (TA3) in rat liver. II. Deiodination and conjugation of TA3 by rat hepatocytes and in rats in vivo.

The hepatic metabolism of 3,3',5-triiodothyroacetic acid (TA3), a naturally occurring side-chain analog of T3, was studied in vitro and in vivo. Metabolites were quantified by HPLC after Sephadex LH-20 prepurification of samples obtained after incubation of [125I]TA3 or 3,[3'-125I]diiodothyroacetic acid (3,[3'-125I]TA2) with isolated rat hepatocytes under various conditions or after iv administration of [125I]TA3 to normal or 6-propyl-2-thiouracil (PTU)-treated rats. In protein-free incubations with hepatocytes, TA3 glucuronide (TA3G) and I- were normally the main TA3 products, i.e. 44% and 49%, respectively. In the presence of the type I deiodinase inhibitor PTU, the I- production from added TA3 decreased to 3%, and TA3 sulfate (TA3S) increased from 2-14%. Normally, 3,3'-TA2 was converted to I-, but in the presence of PTU 3,3'-TA2S was produced. In SO4(2-)-depleted cultures incubated with TA3 or 3,3'-TA2, production of I- was diminished, and the glucoronides of the substrates and the deiodinated products were generated. If both sulfation and deiodination were inhibited, TA3 and 3,3'-TA2 were cleared completely via glucuronidation. The metabolism of TA3 and especially 3,3'-TA2 was greatly retarded in cultures with 0.1% BSA. PTU treatment of TA3-injected rats reduced plasma I- levels 6-fold, increased plasma sulfates 2.6-fold, but did not affect plasma TA3 clearance. Biliary excretion of radioactivity until 4 h after [125I]TA3 injection amounted to 55% of the dose in controls vs. 85% in PTU-treated rats. In both groups, an unknown metabolite X was detected in serum and its sulfate conjugate XS in bile. The mean percent distribution of TA3G/TA3S/XS in bile amounted to 70:8:13 in control and 57:22:12 in PTU rats. In conclusion, TA3 is effectively metabolized in rat liver by glucuronidation and subsequent biliary excretion of TA3G, which may explain its rapid in vivo clearance relative to T3. Furthermore, a significant proportion of TA3 is deiodinated by the type I deiodinase, either directly or after prior sulfation.

Animals↗
PubMedDate not supplied

Distribution and disposition of trospectomycin sulfate in the in vivo rat, perfused rat liver, and cultured rat hepatocytes.

Trospectomycin sulfate is an experimental, aminocyclitol antibiotic. It has been shown in preclinical, chronic safety studies in the dog and rat to elicit a reversible, lysosomal phospholipidosis in liver. The present experiments were conducted to characterize the tissue distribution and disposition of 3H]trospectomycin sulfate in the male rat, perfused rat, perfused rat liver, and cultured rat hepatocytes. Following a 5 mg/kg iv dose to four rats, approximately 70% of the dose was recovered within 24 hr primarily in urine as unchanged drug, and the remainder was eliminated with a terminal phase half-life in blood and tissues of 3 days. Fecal excretion was relatively minor (16% of the dose recovered in feces in 7 days) until later timepoints, when it was the principal pathway of terminal phase elimination. The liver sequestered approximately 10% of the dose and had the highest tissue levels of drug at all times measured. Liver perfusion experiments indicated that trospectomycin accumulated in a hepatic depot compartment as parent drug by a first-order process which was nonsaturable up to a 1 mM concentration of drug. Biliary excretion of unchanged trospectomycin by the perfused liver was slow (approximately 3% of the dose in 2 hr) and occurred by both paracellular and transcellular mechanisms. The hepatic depot compartment appeared to be responsible for transcellular biliary excretion, and thus for the sustained fecal excretion observed in vivo. Subcellular distribution experiments indicated that at least 50% of the drug in the hepatic depot was sequestered in organelles having a broad density range. The existence of a trospectomycin depot compartment was also demonstrated in cultured hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗