Plasma norepinephrine in humans: limitations in assessment of whole body norepinephrine kinetics and plasma clearance

1989 ◽  
Vol 257 (5) ◽  
pp. E743-E750 ◽  
Author(s):  
J. H. Henriksen ◽  
N. J. Christensen
Keyword(s):  
Plasma Concentration ◽  
Infusion Rate ◽  
Plasma Clearance ◽  
Whole Body ◽  
Plasma Norepinephrine ◽  
Metabolic Clearance ◽  
Infusion Time ◽  
Total Plasma ◽  
Straight Line ◽  
Body Clearance

To investigate catecholamine residence in plasma, constant intravenous infusions of increasing duration (20, 40, and 80 min) of [3H]norepinephrine [( 3H]NE), [3H]isoproterenol [( 3H]IP) IP) and a reference substance: 131I-labeled hippurate were performed in six normal volunteers. In contrast to [3H]IP and 131I-hippurate, whole body clearance from plasma of [3H]NE, as obtained from infusion rate divided by plasma concentration of tracer [1.74 +/- 0.64 (SD) 1/min] was significantly higher than the value obtained by total tracer infusion divided by total plasma area of tracer (1.27 +/- 0.51, P less than 0.01). Mean residence time in plasma (theta) after stopping the infusion of [3H]NE increased along an almost straight line with progressive infusion time, theta of 131I-hippurate increased less, and constant values were recorded after 40 min infusion of [3H]IP. Our results suggest the presence of a very large (cellular) pool from which a reversible transport of [3H]NE back into plasma takes place. The plasma clearance of tracer NE, as determined from infusion rate and plasma concentration of tracer, includes transport to and accumulation in this large store. Thus the "final metabolic clearance," reflecting irreversible removal of NE, is smaller than previously estimated due to recycling through the plasma space. Attention has been drawn to limitations of [3H]NE kinetics.

Impact of the Herbal Breviscapine on the Pharmacokinetics of Simvastatin in Rats: The Involvement of CYP3A4

Drug Research ◽  
2017 ◽  
Vol 67 (05) ◽  
pp. 271-274 ◽  
Author(s):  
Aixia Ju ◽  
Yang Li ◽  
Zhe Qu ◽  
Qiuhong Li
Keyword(s):  
Plasma Concentration ◽  
Mrna Expression ◽  
Plasma Clearance ◽  
Adverse Reactions ◽  
Saline Solution ◽  
Total Plasma ◽  
Total Plasma Clearance ◽  
Combined Use ◽  
Pre Treatment ◽  
Hepatic Cytochrome

AbstractThe effect of breviscapine injection on the pharmacokinetics of simvastatin and the mRNA expression of hepatic cytochrome P450 (CYP) enzyme was investigated with rats. The rats were pretreated for 8 consecutive days with breviscapine injection (20 mg/kg/day, i. v.), followed by administration of simvastatin through gavage (40 mg/kg). The control rats received the corresponding volume of saline solution for the pretreatment. Blood samples were collected at varied time points after simvastatin administration and the liver was harvested after the last collection of the blood sample for measurement of the CYP3A4 mRNA expression. Pre-treatment with breviscapine injection led to increased plasma concentration of simvastatin, showing 57% increase for AUC0-∞ (P<0.01), 31% increase for C max (P<0.01), and 36% decrease for the total plasma clearance, compared with the control. Pre-treatment with breviscapine injection also inhibited the mRNA expression of the hepatic CYP3A4. These findings indicate that pre-treatment with breviscapine injection could increase the plasma concentration of simvastatin, possibly by inhibiting the expression of the hepatic CYP3A4, and combined use of breviscapine with simvastatin may improve the simvastatin efficacy and reduce its adverse reactions through reduced its dosage.

Continuous Estimation of CO2 Production during Exercise

1997 ◽  
Vol 36 (04/05) ◽  
pp. 368-371
Author(s):  
R. Soma ◽  
Y. Yamamoto
Keyword(s):  
Fuzzy Logic ◽  
Steady State ◽  
Infusion Rate ◽  
Feedback System ◽  
Whole Body ◽  
Co2 Production ◽  
Cycle Exercise ◽  
Continuous Estimation ◽  
Breath Measurement ◽  
13Co2 Enrichment

Abstract.A new method was developed for continuous isotopic estimation of human whole body CO2 rate of appearance (Ra) during non-steady state exercise. The technique consisted of a breath-by-breath measurement of 13CO2 enrichment (E) and a real-time fuzzy logic feedback system which controlled NaH13CO3 infusion rate to achieve an isotopic steady state. Ra was estimated from the isotope infusion rate and body 13CO2 enrichment which was equal to E at the isotopic steady state. During a non-steady state incremental cycle exercise (5 w/min or 10 w/min), NaH13CO3 infusion rate was successfully increased by the action of feedback controller so as to keep E constant.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

ANDROGEN METABOLISM IN CONGENITAL ADRENAL HYPERPLASIA DUE TO 11 β-HYDROXYLASE DEFICIENCY

PEDIATRICS ◽  
1969 ◽  
Vol 44 (2) ◽  
pp. 201-208
Author(s):  
S. Douglas Frasier ◽  
Richard Horton ◽  
Robert A. Ulstrom
Keyword(s):  
Plasma Concentration ◽  
Urinary Excretion ◽  
Congenital Adrenal Hyperplasia ◽  
Conversion Ratio ◽  
Metabolic Clearance ◽  
Adrenal Hyperplasia ◽  
Metabolic Clearance Rate ◽  
Hydroxylase Deficiency ◽  
Glucocorticoid Administration

The plasma concentration of androstenedione and testosterone, metabolic clearance rate of androstenedione, and in vivo conversion ratio of androstenedione to testosterone have been studied in a normotensive 5-year-old female with congenital adrenal hyperplasia due to a deficiency of 11 β-hydroxylase. Prior to glucocorticoid administration, the urinary excretion of 17-ketosteroids varied from 2.2 to 4.9 mg/24 hours, urinary excretion of pregnanetriol varied from 0.7 to 2.2 mg/24 hours, and total 17-hydroxysteroid excretion varied from 1.2 to 7.5 mg/24 hours. Urinary tetrahydro-11-deoxy cortisol (TSH) was detected at a concentration of 550 µg/24 hours. The plasma concentration of androstenedione varied from 100 to 530 mµg/100 ml and the plasma concentration of testosterone varied from 40 to 90 mµg/100 ml. These values are significantly elevated when compared to those obtained in normal prepubertal females. Urinary steroid excretion and plasma androgen concentrations fell to normal in response to glucocorticoid administration. The metabolic clearance rate of androstenedione was 890 liters per day per M2 and the in vivo conversion ratio of androstenedione to testosterone was 11%. The calculated production rate of androstenedione was 4.7 mg per day per M2. Virilization in congenital adrenal hyperplasia due to 11 β-hydroxylase deficiency can be explained by an elevated plasma concentration of testosterone, which can be accounted for on the basis of conversion from androstenedione.

Acute Effects of Acetazolamide (Diamox) on Plasma and Urinary Electrolytes of Dogs With Special Reference to Calcium

1957 ◽  
Vol 191 (2) ◽  
pp. 388-392 ◽  
Author(s):  
Smith Freeman ◽  
Anne B. Jacobsen
Keyword(s):  
Carbon Dioxide ◽  
Plasma Concentration ◽  
Chloride Concentration ◽  
Total Plasma ◽  
Acute Effects ◽  
Plasma Phosphate ◽  
Sodium Potassium ◽  
Excretory Function ◽  
Acute Increase ◽  
Renal Excretory Function

Administration of Diamox by ingestion or injection to adult fasting female dogs consistently produced an acute increase of approximately 1 mg % in the plasma concentration of calcium. At the same time there was an increase in the plasma phosphate and chloride concentration and a decrease in total plasma content of carbon dioxide of Diamox-infused dogs. Diamox did not affect the plasma concentration of calcium, chloride or bicarbonate if renal excretory function was abolished prior to its administration. Infusion of Diamox produced a prompt rise in the urinary excretion of sodium, potassium, calcium, phosphate, citrate, chloride and water in fasting female dogs. The effect of Diamox on the fasting concentration of calcium rendered unsatisfactory the interpretation of data concerned with a study of its effect on the disappearance of injected calcium. However, intravenous injection of small amounts of sodium carbonate was found to produce a definite delay in the rate of disappearance of injected calcium.

scholarly journals Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

2009 ◽  
Vol 296 (1) ◽  
pp. E105-E113 ◽  
Author(s):  
Olasunkanmi A. J. Adegoke ◽  
Stéphanie Chevalier ◽  
José A. Morais ◽  
Réjeanne Gougeon ◽  
Scot R. Kimball ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Whole Body ◽  
Glucose Disposal ◽  
Metabolic Clearance ◽  
Cellular Mechanisms ◽  
Body Protein ◽  
Fed State ◽  
Mtorc1 Signaling

Since maximum anabolism occurs postprandially, we developed a simulated fed state with clamped hyperinsulinemia, physiological hyperglycemia, and hyperaminoacidemia (Hyper-3) and explored muscle cellular mechanisms. Whole body [1-13C]leucine and [3-3H]glucose kinetics in healthy men were compared between hyperinsulinemic, euglycemic, isoaminoacidemic (Hyper-1, n = 10) and Hyper-3 ( n = 9) clamps. In Hyper-3 vs. Hyper-1, nonoxidative leucine Rd [rate of disappearance (synthesis)] was stimulated more (45 ± 4 vs. 24 ± 4 μmol/min, P < 0.01) and endogenous Ra [rate of appearance (breakdown)] was inhibited similarly; hence net balance increased more (86 ± 6 vs. 49 ± 2 μmol/min, P < 0.001). Glucose Rd was similar; thus Hyper-3 metabolic clearance rate (331 ± 23 vs. 557 ± 41 ml/min, P < 0.0005) and Rd/insulin (M, 0.65 ± 0.10 vs. 1.25 ± 0.10 mg·min−1·pmol−1·l, P < 0.001) were less, despite higher insulin (798 ± 74 vs. 450 ± 24 pmol/l, P < 0.005). In vastus lateralis muscle biopsies, phosphorylation of Akt ( P = 0.025), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K1; P = 0.008), S6 ( P = 0.049), and 4E-binding protein 1 (4E-BP1; P = 0.001) increased. With decreased eukaryotic initiation factor-4E (eIF4E)·4E-BP1 complex ( P = 0.01), these are consistent with increased mTOR complex 1 (mTORC1) signaling and translation initiation of protein synthesis. Although mRNA expression of ubiquitin, MAFbx 1, and MuRF-1 was unchanged, total ubiquitinated proteins decreased 20% ( P < 0.01), consistent with proteolysis suppression. The Hyper-3 clamp increases whole body protein synthesis, net anabolism, and muscle protein translation initiation pathways and decreases protein ubiquitination. The main contribution of hyperaminoacidemia is stimulation of synthesis rather than inhibition of proteolysis, and it attenuates the expected increment of glucose disposal.

Endocrinologic and metabolic effects of interleukin-6 in humans

1995 ◽  
Vol 268 (5) ◽  
pp. E813-E819 ◽  
Author(s):  
J. M. Stouthard ◽  
J. A. Romijn ◽  
T. Van der Poll ◽  
E. Endert ◽  
S. Klein ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Interleukin 6 ◽  
Cell Cancer ◽  
Metabolic Effects ◽  
Isotope Dilution Method ◽  
Saline Control ◽  
Dilution Method ◽  
Plasma Norepinephrine ◽  
Metabolic Clearance

Interleukin-6 (IL-6) is one of the major circulating cytokines in catabolic states. To investigate its endocrinologic and metabolic actions in vivo, we studied eight patients with metastatic renal cell cancer two times, once during infusion of saline (control) and once during a 4-h infusion of 150 micrograms recombinant human IL-6 (rhIL-6). Rates of appearance (Ra) of glucose and free fatty acids (FFA) in plasma were measured by using the isotope dilution method. Energy expenditure and substrate oxidation were determined by indirect calorimetry. rhIL-6 induced increases in plasma norepinephrine (+261 +/- 97%, P < 0.001), cortisol (+210 +/- 48%, P < 0.001), and glucagon (+70 +/- 18%, P < 0.001), in resting energy expenditure (+25 +/- 2%, P < 0.001 vs. control), and in plasma FFA concentration (+60 +/- 30%, P < 0.001), FFA Ra (+105 +/- 18%, P < 0.001), and fat oxidation (+38 +/- 16%, P < 0.001). Glucose Ra increased by 20 +/- 5% (P < 0.01) during rhIL-6 infusion with a concomitant increase in the metabolic clearance rate of glucose. In conclusion, our data demonstrate that rhIL-6 induces many of the endocrinologic and metabolic changes found in catabolic states and thus may mediate some of the metabolic effects previously ascribed to other cytokines.

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