Plasma Concentration Rate Research Articles

High-performance liquid chromatographic procedure for the determination of rat plasma concentrations of a new antibacterial agent, (±)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1 H,5 H-benzo[ i,j]quinolizine-2-carboxylic acid, for topical use

High-performance liquid chromatographic procedure for the determination of rat plasma concentrations of a new antibacterial agent, (±)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1 H,5 H-benzo[ i,j]quinolizine-2-carboxylic acid, for topical use

Determination of Diphenhydramine in Rat Milk and Plasma and Its Effects on Milk Composition and Mammary Gland Nucleic Acids

To study the excretion of diphenhydramine into rat milk, milk and plasma concentrations of diphenhydramine were determined in lactating rats after single or multiple oral doses. Four hours after a single dose of 40 or 100 mg/kg of diphenhydramine, milk concentrations of the drug averaged 0.30 and 2.2 micrograms/mL, respectively, in two experiments, and the milk:plasma ratios ranged from 4.4 to 7.5. Multiple doses did not significantly affect the plasma or milk concentrations or the milk:plasma ratios, which were similar to the theoretical milk:plasma ratio based on pH partitioning for this compound (i.e., 4.0). Although the concentration of diphenhydramine was higher in milk than in plasma, the estimated dose received by the pups (0.057 mg/kg/d) based on the milk concentrations was much lower than that given to the mother. Oral diphenhydramine treatment at doses which significantly reduced maternal food consumption had no effect on milk solid, lipid, protein, or lactose concentrations, nor on mammary gland RNA or DNA content, indicating that diphenhydramine did not adversely affect lactation.

Variations in immunocytochemical localization of cathepsin B and thyroxine in follicular cells of the rat thyroid gland and plasma TSH concentrations over 24 hours.

Immunocytochemical localization of cathepsin B and thyroxine (T4) in follicular cells of the rat thyroid gland and plasma concentrations of thyroid stimulating hormone (TSH) were examined at six evenly spaced times over 24 h. By light- and electron microscopy, immunodeposits for cathepsin B were localized in cytoplasmic granules of various sizes, whereas those for T4 were detected mainly in larger granules of the cells and in the colloid lumen. The size and location of cytoplasmic granules showing immunoreactivity for cathepsin B and T4 in the cells varied over 24 h, corresponding to a change in plasma TSH concentrations. These immunopositive large granules appeared in the apical cytoplasm at 12.00 h, when the level of TSH was highest. At 20.00 h when the level of TSH was lowest, T4-positive granules almost disappeared, and cathepsin B-positive small granules were abundantly seen in the basal region. From 00.00 h to 08.00 h, these positive granules changed in the same manner as those seen from 12.00 h to 20.00 h, associated with an increase in plasma TSH levels. These results suggest that newly formed colloid droplets migrate from the apical to the basal regions. Cathepsin B may play a role not only in the degradation of thyroglobulin but in the maturation of thyroid hormones during the migration of the granules.

Plasma, cardiac tissue and brain morphine concentrations in acute and chronic morphine-treated rats.

1. The plasma, cardiac tissues and brain morphine concentrations in rats after acute or chronic morphine treatment were measured by high-performance liquid chromatography. 2. Morphine concentrations in plasma and cardiac tissues were found to be significantly higher than those in brain after acute morphine injection. However, after chronic oral administration, morphine concentrations in plasma, cardiac tissues and brain were similar. 3. Brain concentrations of morphine following chronic administration were higher than those obtained after acute administration although concentrations in plasma and cardiac tissues were lower.

ANF inhibits NaCl and fluid absorption in cortical collecting duct of rat kidney

Atrial natriuretic factor (ANF) is a peptide hormone that causes a large increase in urinary sodium chloride and water excretion when its plasma concentration rises above basal levels. As yet, there is no consensus regarding the chief site of action of ANF in the kidney. We microdissected and perfused rat cortical collecting ducts in vitro to determine whether ANF-(1-28) can directly inhibit net sodium and fluid absorption. ANF decreased both net sodium absorption and vasopressin-stimulated net fluid absorption by 50-90% when added to the peritubular bath solution. Approximately 50% inhibition of net fluid absorption occurred at 0.1 nM ANF, a level equivalent to plasma concentrations in volume-expanded rats. The action of ANF was mimicked by the addition of exogenous guanosine 3',5'-cyclic monophosphate. If ANF has a similar action on the cortical collecting duct in vivo, it could account for a substantial part of the ANF-mediated increase in urinary sodium and water excretion.

Determination of AL01576 Concentration in Rat Lenses and Plasma by Bioassay for Aldose Reductase Activity Measurements

Investigations on the disposition of the highly effective aldose reductase inhibitor AL01576 were carried out in pigmented rats after oral dosing and topical administration of a 0.1% ophthalmic suspension by means of an assay modified from a previously described method measuring aldose reductase activity. The crude enzyme extract of pig lenses was used as a test system. From the activity remaining after addition of the plasma or lens extracts, the concentration could be determined since the inhibition constant (IC50) of AL01576 is known. With this procedure, the concentration of AL01576 in plasma and lenses of Brown-Norway rats given different doses of the drug for 42 consecutive days were determined and compared with a gas chromatographic assay technique. These data indicate that AL01576 is absorbed into the lens with a substantial portion redistributing into the lens following systemic delivery. Drug concentrations were correlated with efficacy measurements, though they were lower in an animal group treated with naphthalene to provoke cataract formation. In a second animal series with Brown-Norway rats over 5 days, AL01576 was administered three times per day to the right eye only. During the washout period, AL01576 had a long persistence in plasma and lenses following this short-term topical ocular administration.

Intraocular transplants of a human gastrinoma in immuno-suppressed rats: morphological, chromatographic and functional studies

Tissue pieces of a metastatic human gastrinoma (ultrastructural Type II) were successfully transplanted to the anterior eye-chamber of rats immunosuppressed with Cyclosporin A. Immunocytochemical investigation of the transplants showed evidence for preserved endocrine activity of tumour cells with immunoreactivity towards the C-terminal of the gastrin/cholecystokinin molecule. Studies of gastric acid secretion in tumour-bearing rats and sham-operated controls with chronic gastric fistulas showed that the basal acid output did not differ between the groups during 3 weeks of study. However, the stimulated gastric acid secretion decreased after 5 days in both groups to remain significantly depressed throughout the study, an effect probably due to Cyclosporin A treatment of the groups. The concentration of immunoreactive gastrin in plasma from rats with tumours in oculo was 5 times higher than in sham-operated rats. Gastrin-34 was the major immunoreactive component in both patient serum and rat plasma. An immunoreactive fraction corresponding to component I was found in the patient serum, but not in the rat plasma, although present in the chamber fluid. Components corresponding to gastrin-17 were found both in the patient serum and in the rat plasma. The chromatographic pattern of the tumour was similar to that in rat chamber fluid. The dominating component corresponded to gastrin-17, while gastrin-34 represented the quantitatively smaller component. Gastrin-34 was, however, relatively more abundant in the tumour extract than in the chamber fluid. The study also indicates that a gastrin-producing tumour transplanted in oculo in immunosuppressed rats may increase the rat plasma concentration of the same molecular forms of gastrin as seen in the clinical situation.

Quantitative analyses of atrial myoendocrine cells and plasma atrial natriuretic peptides (ANP) of the rat with special reference to the twenty-four-hour variations in secretory granules and plasma ANP concentrations.

Subcellular structures of atrial myoendocrine cells in the rat heart and plasma concentrations of atrial natriuretic peptides (ANP) were examined at six evenly-spaced time points over 24 h, using morphometric techniques and radioimmunoassay. Myofibrils and mitochondria of the cells occupied 73.3% of the cytoplasm; 2% of the cytoplasm was occupied by secretory granules, rough endoplasmic reticulum and Golgi complexes, structures characteristic of endocrine cells. Plasma ANP concentration was maximal at 08.00 h, when the individual volume of secretory granules was minimal. The numerical density of secretory granules was increased at 12.00 h. The plasma ANP concentration was minimal at 20.00 h, when the numerical density was minimal and the individual volume was maximal. The fluctuation in plasma ANP concentrations over 24 h was thus parallel to that in the numerical densities of secretory granules and inverse to that in individual volumes. These results suggest that in rats the secretory activity of atrial myoendocrine cells increases at the beginning of the resting period, whereas it decreases at the beginning of the active phase.

Percutaneous absorption of diclofenac in rats and humans: aqueous gel formulation

The rat dorsal percutaneous absorption of sodium diclofenac increased with an increase in sodium diclofenac concentration in an applied aqueous solution, but the bioavailability was poor. The addition of 10% w/w ethanol in the aqueous solution containing sodium diclofenac apparently increased the percutaneous absorption of diclofenac, which was performed by the increase in the sodium diclofenac concentration in the applied, solution rather than by an increase in dorsal skin permeability to diclofenac. The administration of sodium diclofenac in the aqueous gel formulation, which was prepared with hydrogenated soya phospholipid, increased the plasma diclofenac concentration in rat significantly. The formulation causing high diclofenac concentration in rat plasma also resulted in a large accumulation of diclofenac in the dorsal subcutaneous tissue. The dorsal percutaneous administration of sodium diclofenac in the aqueous gel form to healthy human subjects caused a gradual increase of plasma diclofenac concentration during the experimental period of 8 h. The relative bioavailability of sodium diclofenac in the gel form in one subject was about 7% of that after rectal administration of a commercial suppository of sodium diclofenac.

I.r. β-endorphin, corticosterone, cholesterol and triglyceride concentrations in rat plasma after stress, cingulotomy or both

Plasma i.r. β-endorphin, corticosterone, cholesterol and triglyceride concentrations were determined in male Sprague-Dawley rats after exposure to running or swimming stressors or after surgical ablation of the cingulum bundle. While cingulotomy alone altered only the plasma triglyceride concentrations, the combination of cingulotomy plus running stress significantly increased plasma i.r. β-endorphin and triglyceride concentrations above those seen in animals receiving only a running stress. Triglyceride concentrations in cingulotomy plus swimming stress were significantly elevated above those in animals receiving a severe stress only. While the exposure to running and swimming increased plasma β-endorphin significantly above control levels, plasma corticosterone was not affected by these stressors. Changes in plasma cholesterol and triglycerides were also differentially affected by cingulotomy or stress exposure. These results indicate that various stress hormones are affected differentially by exposure to various experimental procedures which are employed as stressors.

IGF-1 concentrations in protein deficient rat plasma and tissues in relation to protein and proteoglycan synthesis rates

IGF-1 concentrations in protein deficient rat plasma and tissues in relation to protein and proteoglycan synthesis rates

Oat Fiber: Composition versus Physiological Function in Rats

The effect of processing on the ability of oat fiber to lower plasma and liver cholesterol concentrations in rats was studied. Male Sprague-Dawley rats were fed diets containing 6% dietary fiber as cellulose, oat bran, high fiber oat flour or one of four processed high fiber oat flours for 3 wk. All diets also contained 1.0% cholesterol and 0.2% cholic acid. At the conclusion plasma and liver concentrations of cholesterol and triglycerides were measured. All of the oat products significantly lowered plasma and liver cholesterol without depressing food intake or weight gain. As little as 4% dietary fiber in a processed oat flour significantly lowered cholesterol concentrations. Detailed fiber analysis of all of the oat fiber products revealed that processing increased the proportion of the total fiber that was soluble. The proportions recovered as total beta-glucans and total neutral sugars also increased, in part because the proportion recovered as Klason lignin decreased in all of the processed oat flours except the one prepared by a high pressure extrusion process.

Drug interactions between imipramine and benzodiazepines in rats

The concomitant administration of diazepam and imipramine hydrochloride increased desipramine concentration in rat plasma, but decreased 2-hydroxyimipramine and 2-hydroxydesipramine concentrations; the concomitant administration of oxazepam and imipramine hydrochloride decreased imipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine concentrations. Imipramine plasma protein binding was unaltered in all cases. Liver concentrations of imipramine and 2-hydroxydesipramine were increased by concomitant administration of oxazepam and imipramine hydrochloride. Concomitant administration of benzodiazepines and imipramine hydrochloride increased imipramine concentration in the brain. The effects of imipramine hydrochloride on hypothermia induced by reserpine, and on behavioral despair in rats was also studied. The concomitant administration of diazepam and imipramine hydrochloride led to a decrease in the anti-reserpine effect of imipramine hydrochloride and in the imipramine hydrochloride-induced recovery from immobility in the forced swimming test. These results are in accord with the findings on brain concentrations of imipramine and its metabolites.

Gentamicin plasma concentrations in pregnant and non-pregnant rats and fetuses after single and multiple injections

As part of our studies on the prenatal induction of renal dysfunctions in rats by gentamicin we measured maternal plasma levels of the drug. Additionally, the gentamicin concentrations in the plasma of rat fetuses after single s.c. injections of gentamicin were measured. The following results were obtained: 1) Non-pregnant rats excrete the drug faster than pregnant rats; 2) after a single s.c. injection of 110 mg gentamicin/kg body wt to six pregnant rats on day 21 of gestation the following pharmacokinetic variables were calculated: t1/2(inv): 27.0 +/- 6.1 min, t1/2(elim): 54.7 +/- 3.8 min, Cmax: 166.2 +/- 22.7 mg/l, tmax: 53 +/- 6.7 min, AUC: 431.7 +/- 53.4 mg/l x h; 3) plasma concentrations increase with the duration of pregnancy; 4) fetal plasma concentrations were determined between 45 and 660 min after single injections of 150 mg/kg to the dams. The concentrations showed minimum variation over this time period. Thus, the ratio of maternal to fetal plasma levels decreases drastically during this period; 5) 8 h after s.c. injection of 110 mg/kg to six dams (day 21 of gestation) individual plasma concentrations in the plasma of mother animals and in the plasma of 65 fetuses were determined. All fetal plasma samples showed higher concentrations than the corresponding maternal ones; 6) after multiple injections a significant increase in plasma concentrations can be seen. A considerable individual variance is obvious at all times and with both doses investigated; 7) since maternal plasma concentrations vary considerably in individual animals, especially after multiple injections, fetal exposure must also be variable in different litters. This would also affect the extent of postnatal dysfunction in various litters.

Metabolic fate of recombinant human tissue plasminogen activator(rt-PA). (1): Blood or plasma concentration, distribution, metabolism and excretion in rats after single intravenous administration.

125I-rt-PAを雌雄ラットに単回静脈内投与した時の，rt-PAの血中濃度推移，分布，代謝および排泄について検討した．以下にその要約を示す． 1．125I-rt-PA静脈内投与後，血漿中の未変化rt-PA濃度，免疫反応性rt-PA濃度および線溶活性は速やかに消失した．血漿中には125I-rt-PAとα2-macroglobulin，またはα2-antiplasminとの複合体の存在が示唆された． 2．125I-rt-PA静脈内投与後，肝臓，脾臓，骨髄，副腎，腎臓，血漿に高い放射能の分布が認められた．その他の臓器中の放射能濃度は血液中濃度より低値であった．これら臓器中の放射能の大部分はTCA沈澱性の放射能であり，投与後総放射能濃度よりも速やかに減少した．投与後5minの肝臓および腎臓中に免疫反応性が認められたが，その消失は血漿中と同様に速やかであった． 3．125I-rt-PA静脈内投与後120hrまでに，投与した放射能の89%および5～6%がそれぞれ尿および糞中に排泄された．また投与後48hrまでに，投与放射能の15%が胆汁中に排泄された．

Metabolic fate of recombinant human tissue plasminogen activator(rt-PA). (2): Blood or plasma concentration, distribution, metabolism, excretion and accumulation in rats after repeated intravenous administration.

Blood or plasma concentration, distribution, metabolism, excretion and accumulation of rt-PA were investigated in male rats after repeated intravenous administration of 125I-rt-PA for 15 days. 1. During the repeated intravenous administration of 125I-rt-PA, blood or plasma total radioactivity, radioactivity in TCA precipitate, immunoreactive rt-PA, fibrinolytic activity, unchanged rt-PA and its metabolites were constant at 5 min after each dosing. After the repeated intravenous administration of 125I-rt-PA for15 days, blood or plasma total radioactivity and radioactivity in TCA precipitate decreased slower than those after single administration, but decline of the immunoreactive rt-PA level and fibrinolytic activity were same as those after single administration. 2. During the repeated intravenous administration of 125I-rt-PA, the radioactivity in organs at 24 hr after each dosing increased gradually till 5 th or 10 th days and remained almost constant till 15 th day. After repeated intravenous administration of 125I-rt-PA for 15 days, the total radioactivity and radioactivity in TCA precipitate in each organ decreased slowly than those after single administration. At 5 min after each dosing, immunoreactive rt-PA levels in the liver and kidney were unchanged during the repeated administration. There was no clear indication of accumulation of rt-PA. 3. The excretion of radioactivity in the urine and feces was nearly the same throughout the period of repeated intravenous administration of 125I-rt-PA. Within 120 hr after the last dosing, 90 % and 8 % of the administered radioactivity excreted into the urine and feces, respectively.

Effects of hemorrhagic hypotension on tyrosine concentrations in rat spinal cord and plasma

Tyrosine is the precursor for catecholamine neurotransmitters. When catecholamine-containing neurons are physiologically active (as sympathoadrenal cells are in hypotension), tyrosine administration increases catecholamine synthesis and release. Since hypotension can alter plasma amino acid composition, we examined the effects of an acute hypotensive insult on tyrosine concentrations in plasma and spinal cord. Rats were cannulated and bled until the systolic blood pressure was 50 mmHg, or were kept normotensive for 1 h. Tyrosine and other large neutral amino acids (LNAA) known to compete with tyrosine for brain uptake were assayed in plasma and spinal cord. The rate at which intra-arterial [ 3H]tyrosine disappeared from the plasma was also estimated in hemorrhaged and control rats. In plasma of hemorrhaged animals, both the tyrosine concentration and the tyrosine/LNAA ratio was elevated; moreover, the disappearance of [ 3H]tyrosine was slowed. Tyrosine concentrations also increased in spinal cords of hemorrhaged-hypotensive rats when compared to normotensive controls. Changes in plasma amino acid patterns may thus influence spinal cord concentrations of amino acid precursors for neurotransmitters during the stress of hemorrhagic shock.

Binding of glycyrrhetinic acid to rat plasma, rat serum albumin, human serum, and human serum albumin.

The binding of glycyrrhetinic acid (GLA) to rat plasma, rat serum albumin (RSA), human serum, and human serum albumin (HSA) was examined by an ultrafiltration technique. Specific and nonspecific bindings were observed in all cases. The assosiation constant (K) for the specific binding was 1.34 × 105 M-1 in rat plasma and 1.56 × 105 M-1 in RSA. The K value for human serum (14.91 × 105 M-1) and that for HSA (15.09 × 105 M-1) were approximately 10-fold larger than those for rat plasma and RSA, suggesting a species difference in the specific binding affinity for GLA. The number of specific binding sites (n) was 2.49 and 1.18 for RSA and HSA, respectively. The linear binding coefficient (ψ) for the nonspecific binding was 7.11 × 103 M-1 in RSA and 6.57 × 103 M-1 in HSA.When the rat plasma and human serum protein concentrations are respectively assumed to be 3.5% and 4.2% (equal to the measured plasma and serum albumin concentrations), n was 1.83 in rat plasma and 1.31 in human serum, which corresponded fairly well to those for RSA and HSA. Further, for ψ in rat plasma and human serum, when rat plasma and human serum protein are the measured albumin concentrations, respectively, ψ was 10.97 × 103 M-1 for rat plasma and 14.83 × 103 M-1 for human serum, which corresponded well to those for RSA and HSA.It was concluded that the GLA-binding sites in rat plasma and human serum exist in albumin and GLA binds to specific and nonspecific binding sites at lower and higher concentrations than approximately 2 mM, respectively.

Imipramine Treatment Alters the Pharmacokinetics and Pharmacodynamics of Diazepam

This report describes observations of the relationship between the pharmacokinetics and pharmacodynamics of diazepam (7-chioro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; 5 mg/kg) during the concomitant administration of diazepam and imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride; 20 and 50 mg/kg) to rats. We measured plasma, brain, and liver concentrations of diazepam and its metabolites in rats by high-performance liquid chromatography. The concomitant use of imipramine hydrochloride increased diazepam and desmethyldiazepam concentrations, but decreased temazepam and oxazepam concentrations in rat plasma. Diazepam plasma protein binding was unaltered. The liver concentrations of diazepam and its metabolites showed similar changes in their plasma concentrations. The concomitant use of imipramine hydrochloride increased the concentrations of diazepam and its metabolites in the brain. We also studied the effect of benzodiazepines on convulsions induced by pentylenetetrazole (6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a] azepine; 135 mg/kg) in rats. The concomitant use of imipramine hydrochloride led to an increased anti-pentylenetetrazole effect of diazepam. This result is in accordance with the findings on brain concentrations of diazepam and its metabolites.

Alpha 1-adrenergic effects and liver regeneration.

The effects of several treatments involving alpha-adrenergic mechanisms upon the early stages of rat liver regeneration were examined. Catecholamine concentrations in rat plasma were measured at various times after hepatectomy and were found to be elevated relative to those in plasma from sham-operated rats. Surgical hepatic denervation or injection of an alpha 1-adrenergic receptor antagonist (prazosin) reduced incorporation of [3H]thymidine into liver DNA during the first 24 hr after partial hepatectomy. Chronic guanethidine injections (3 to 6 weeks) reduced liver catecholamine levels, but did not affect its ability to regenerate. The inhibition of regenerative DNA synthesis by prazosin was preceded by an alteration in the binding of epidermal growth factor to regenerating liver, which was apparently the result of an increased number of epidermal growth factor receptors. Thus, alpha 1-adrenergic blockade, which affects both epidermal growth factor receptor binding and subsequent DNA synthesis in hepatocyte primary cultures, can also modulate these processes during liver regeneration in vivo.