Correlation between quinolone uptakes by BCECs in vitro and brain-to-plasma concentration ratios in rats

2005 ◽  
Vol 30 (4) ◽  
pp. 249-254 ◽  
Author(s):  
X. D. Liu ◽  
D. W. Wang ◽  
L. Xie
Keyword(s):  
Plasma Concentration ◽  
Concentration Ratios

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Passively immunizing ewes against inhibin during the luteal phase of the oestrous cycle raises the plasma concentration of FSH

1989 ◽  
Vol 123 (3) ◽  
pp. 383-391 ◽  
Author(s):  
G. E. Mann ◽  
B. K. Campbell ◽  
A. S. McNeilly ◽  
D. T. Baird
Keyword(s):  
Plasma Concentration ◽  
Luteal Phase ◽  
Passive Immunization ◽  
Oestrous Cycle ◽  
Ovulation Rate ◽  
Control Group ◽  
Pituitary Cells ◽  
Marked Rise ◽  
Peripheral Plasma

ABSTRACT Passive immunization was used to investigate the importance of inhibin in the negative feedback loop regulating the production of FSH in sheep. An antiserum raised to the 1–26 peptide fragment of the N-terminus of the α-chain of porcine inhibin was first shown to neutralize the suppressive effects of inhibin on the production of FSH by dispersed ovine pituitary cells in vitro. Groups of five mature Scottish Blackface ewes on day 8 of the luteal phase of the oestrous cycle were then injected with either 10 ml plasma from normal ewes (control) or 10 ml ovine inhibin antiserum. On day 10, luteal regression was induced by an i.m. injection of cloprostenol (100 μg), and ovulation rate determined 6 days later by laparoscopy. Peripheral plasma samples were collected throughout the experimental period. Following treatment, there was no change in the peripheral plasma concentration of LH in either group. Following injection of the inhibin antiserum, the concentration of FSH rose significantly (P<0·001) compared with the control group. The concentration of FSH rose from 1·42 ± 0·06 to a maximum of 2·58 ± 0·23 (s.e.m.) μg/l by 5·6 ±0·9 h, this maximum lasting 9·0±1·1 h. By 32·8 ±6·9 h, the concentration of FSH had returned to pretreatment levels, while the titre of free antibody in the plasma of treated ewes was still high. In the treated ewes, there were one single and four double ovulations compared with three single and two double ovulations in the control group, indicating that the inhibin immunization may have resulted in an increase in ovulation rate. We conclude that the marked rise in the plasma concentration of FSH following injection of inhibin antiserum provides strong evidence that inhibin is an important factor in the regulation of FSH production by the pituitary gland at this time. Journal of Endocrinology (1989) 123, 383–391

Preproenkephalin B-derived opioid peptides in human phaeochromocytomas

1987 ◽  
Vol 114 (3) ◽  
pp. 446-451 ◽  
Author(s):  
Toshihiko Yanase ◽  
Hajime Nawata ◽  
Ken-ichi Kato ◽  
Hiroshi Ibayashi
Keyword(s):  
Plasma Concentration ◽  
Opioid Peptides ◽  
Significant Positive Correlation ◽  
Plasma Catecholamines ◽  
Wide Distribution ◽  
Molecular Forms ◽  
Concomitant Increase ◽  
Tissue Contents

Abstract. We demonstrated the presence and the secretion in vivo and in vitro of immunoreactive preproenkephalin B-derived opioid peptides (α-neoendorphin, dynorphin and leumorphin) in human phaeochromocytomas. In senventeen human phaeochromocytomas and two human adrenal medullas, the tissue contents of immunoreactive preproenkephalin B-derived opioid peptides (α-neoendorphin, dynorphin and leumorphin) and leu-enkephalin were studied by specific RIAs. Compared with a remarkable wide distribution in amounts of immunoreactive leu-enkephalin (1063 ± 437 pg/mg, mean ± se), small amounts of immunnoreactive α-neoendorphin (22.6 ± 6.4 pg/mg) and dynorphin (8.5 ± 1.2 pg/mg) were detected in all seventeen human phaeochromocytomas and the two human adrenal medullas. Leumorphin-like immunoreactivity was detected in only four tumours. Gel chromatographic studies revealed the presence of preproenkephalin B-derived peptides and their high molecular forms. A significant positive correlation between the tumour tissue contents of immunoreactive α-neoendorphin and of dynorphin was observed. Nicotine (10−5, 10−4 mol/l) significantly stimulated the secretion of immunoreactive α-neoendorphin and dynorphin as well as leuenkephalin and catecholamines from cultured human phaeochromocytoma cells. Administration of 1 mg of glucagon to a patient with medullary phaeochromocytoma induced a rapid increase in the plasma concentration of immunoreactive α-neoendorphin with a concomitant increase in plasma catecholamines. These results indicate the presence of preproenkephalin B-derived opioid peptides in human phaeochromocytomas and human adrenal medullas and their secretion in human phaeochromocytomas.

17α-HYDROXYLASE DEFICIENCY. A COMBINATION OF HYDROXYLATION DEFECT AND REVERSIBLE BLOCKADE IN ALDOSTERONE BIOSYNTHESIS

1979 ◽  
Vol 90 (3) ◽  
pp. 490-504 ◽  
Author(s):  
D. R. Rovner ◽  
J. W. Conn ◽  
E. L. Cohen ◽  
F. G. Berlinger ◽  
D. C. Kern ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Extracellular Fluid ◽  
Plasma Renin ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Hydroxylase Deficiency ◽  
Resultant Increase

ABSTRACT We have studied the hormonal secretion and excretion patterns in a patient with the XX type of 17α-hydroxylase deficiency. In the untreated state, the patient's urine contained only those steroids which do not require 17-hydroxylation in their biosynthesis. Aldosterone was not produced in the patient and the metabolic product of its immediate precursor, 18-hydroxy-11-dehydro-tetrahydrocorticosterone, was excreted in markedly elevated amounts. This apparent complete block in 18 oxidation was reversible upon long-term ACTH suppression within 27 days. Direct in vitro incubation of the patient's adrenal gland removed at operation demonstrated, 1) the complete lack of 17α-hydroxylase activity, 2) the functional block in the ability to oxidize the hydroxyl group at the 18 methyl side chain. The addition of physiological concentrations of angiotensin to the incubation medium further showed, 3) angiotensin mildly stimulated the entire aldosterone biosynthetic pathway, 4) angiotensin directly stimulated the conversion of 18-hydroxycorticosterone to aldosterone. We propose that in this patient, 17-hydroxylase deficiency produced a decreased plasma concentration of cortisol, followed by stimulation of deoxycorticosterone production by ACTH. The resultant increase in extracellular fluid volume suppressed plasma renin activity. This resulted in a low plasma concentration of angiotensin II which directly suppressed oxidation of 18-hydroxycorticosterone to aldosterone. This defect has been called corticosterone methyl oxidase defect type 2.

scholarly journals Radiocontrast agents induce endothelin release in vivo and in vitro.

1992 ◽  
Vol 3 (1) ◽  
pp. 58-65 ◽  
Author(s):  
S N Heyman ◽  
B A Clark ◽  
N Kaiser ◽  
K Spokes ◽  
S Rosen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasma Concentration ◽  
Plasma Level ◽  
Vascular Endothelium ◽  
Radiocontrast Agent ◽  
Transient Rise ◽  
Bovine Endothelial Cells ◽  
Radiocontrast Agents

The intravascular administration of the ionic radiocontrast agent sodium iothalamate (2.9 g of iodine/kg body wt) to rats induced an increase in plasma concentration of immunoreactive endothelin from 21.3 +/- 1.2 to 36 +/- 3 fmol/mL, preceded by a transient rise in the plasma level of atrial natriuretic peptide and associated with a fall in RBF. Equi-iodine amounts of the nonionic agents ioxaglate and iohexol elicited similar or more marked changes in plasma endothelin, but hypertonic solutions of NaCl, mannitol, or glucose did not. Comparable levels of endothelin produced by infusions of endothelin-1 induced a reduction of up to 29% in RBF. Iothalamate and iohexol stimulated endothelin release from cultured bovine endothelial cells, suggesting a direct effect of ionic and nonionic agents on vascular endothelium. The data invite speculation that under some circumstances endothelin release might play a role in the circulatory changes caused by these compounds and in the pathogenesis of radiocontrast nephropathy.

Plasma concentration profiles for hepatotoxic pyrrolizidine alkaloid senkirkine in humans extrapolated from rat data sets using a simplified physiologically based pharmacokinetic model

2021 ◽  
Vol 15 ◽  
Author(s):  
Yusuke Kamiya ◽  
Tomonori Miura ◽  
Airi Kato ◽  
Norie Murayama ◽  
Makiko Shimizu ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Human Plasma ◽  
In Silico ◽  
Pbpk Model ◽  
Pyrrolizidine Alkaloid ◽  
Water Soluble ◽  
Food Plants ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Aim: The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

scholarly journals Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 978 ◽  
Author(s):  
Ji-Hun Jang ◽  
Seung-Hyun Jeong ◽  
Yong-Bok Lee
Keyword(s):  
Plasma Concentration ◽  
Zeta Potential ◽  
Intravenous Administration ◽  
Half Life ◽  
Encapsulation Efficiency ◽  
In Vitro Release ◽  
Lymphatic Delivery ◽  
Vitro Release ◽  
Lymphatic Targeting

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.

Renal excretion of radiofluoride in the dog

1960 ◽  
Vol 198 (4) ◽  
pp. 829-832 ◽  
Author(s):  
Curtis H. Carlson ◽  
W. D. Armstrong ◽  
Leon Singer ◽  
Lerner B. Hinshaw
Keyword(s):  
Plasma Concentration ◽  
Glomerular Filtration ◽  
Renal Excretion ◽  
Urine Volume ◽  
Urine Concentration ◽  
Tubular Reabsorption ◽  
Carrier Free ◽  
Renal Clearances ◽  
Concentration Ratios

Renal clearances of continuously infused radiofluoride were measured in 10 dogs in which a large part of the skeleton had been excluded from the system in order to produce a more constant plasma radiofluoride concentration. The results were evaluated to describe the factors of glomerular filtration and tubular reabsorption of fluoride under several conditions. The animals that received carrier-free radiofluoride infusions excreted urine with a mean radiofluoride concentration 3.4–14.5 times that of the plasma. The urine-to-plasma concentration ratios obtained with animals given a load of stable fluoride was 13.5–29.6. An increased urine volume resulted in a decreased tubular reabsorption of fluoride and the clearance was increased. Chlorothiazide increased radiofluoride excretion but decreased the urine concentration. The radiofluoride clearances were always less than the creatinine clearances but were 7.8–179 times the chloride clearances. The effect of chlorothiazide was to decrease the ratio of fluoride to chloride clearance by increasing chloride clearance more than fluoride clearance.

Developing a new formulation of sodium phenylbutyrate

2012 ◽  
Vol 97 (12) ◽  
pp. 1081-1085 ◽  
Author(s):  
Nathalie Guffon ◽  
Yves Kibleur ◽  
William Copalu ◽  
C Tissen ◽  
Joerg Breitkreutz
Keyword(s):  
Plasma Concentration ◽  
Healthy Adult ◽  
Taste Perception ◽  
In Vitro Dissolution ◽  
Time Curve ◽  
New Formulation ◽  
Adult Volunteers ◽  
Sodium Phenylbutyrate

BackgroundSodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control.ObjectivesA new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers.ResultsThe in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (Cmax) or for area under the plasma concentration–time curve (AUC). CI for Cmax and AUC0–inf of NaPB were included in the bioequivalence range of 0.80–1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements.ConclusionsIn vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

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