scholarly journals Evidence for Non-Linear Pharmacokinetics of Oxytocin in Anesthetizetized Rat

2008 ◽  
Vol 11 (4) ◽  
pp. 12 ◽  
Author(s):  
Eric Troncy ◽  
Valérie Morin ◽  
Jérôme R.E. Del Castillo ◽  
Simon Authier ◽  
Norma Ybarra ◽  
...  
Keyword(s):  
Central Compartment ◽  
Volume Of Distribution ◽  
Male Rats ◽  
Dosing Regimen ◽  
Linear Pharmacokinetics ◽  
Cardiovascular Therapy ◽  
Elimination Half ◽  
Time Courses ◽  
The Individual ◽  
Higher Doses

Purpose: Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on the cardiovascular and renal systems, we characterized its pharmacokinetic (PK) properties as a function of dose. Methods: A single intravenous bolus of OT was given at doses of 200, 300, 500, 1000, 3000, 5000 and 10000 ng/kg to anesthetized male rats (n >= 4 per dose). Blood samples (6) were taken over 72 min to 150 min, depending on dose. The individual time-courses of plasma OT concentrations were analyzed with a one- or an open two-compartment PK model. Kruskal-Wallis tests (alpha=0.05) were used to compare the PK parameters among groups. Results: At doses up to 500 ng/kg, OT showed a higher median systemic clearance (CLT = 0.0624 L/(min•kg); 0.0622 ± 0.0228 as mean ± SD value), a higher median central compartment volume of distribution (VC = 0.7906 L/kg; 0.6961 ± 0.1754), and a lower median elimination half life (t½(λz) 7.94 min; 9.08 ± 4.3) with respect to the higher doses (CLT = 0.0266 L/(min•kg); 0.0284 ± 0.0098, VC = 0.2213 L/kg; 0.2227 ± 0.1142, and t½(λz) 21.09 min; 28.36 ± 21.8), all differences being significant (p  0.0008). Minimal differences were found for the estimates of these PK parameters among the 4 higher OT doses. Conclusion: The PK properties and persistence of exogenous OT are not proportional to dose, therefore this must be accounted for in dosing regimen design for potential cardiovascular therapy.

Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis

2002 ◽  
Vol 20 (15) ◽  
pp. 3293-3301 ◽  
Author(s):  
Rujia Xie ◽  
Ron H.J. Mathijssen ◽  
Alex Sparreboom ◽  
Jaap Verweij ◽  
Mats O. Karlsson
Keyword(s):  
Tissue Distribution ◽  
Goodness Of Fit ◽  
Population Analysis ◽  
Dose Range ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Clinical Pharmacokinetics ◽  
Lactone Form ◽  
Time Courses

PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m2. The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.

Non–steady State Analysis of the Pharmacokinetic Interaction between Propofol and Remifentanil

2002 ◽  
Vol 97 (6) ◽  
pp. 1350-1362 ◽  
Author(s):  
Thomas Bouillon ◽  
Joergen Bruhn ◽  
Lucian Radu-Radulescu ◽  
Edward Bertaccini ◽  
Sang Park ◽  
...  
Keyword(s):  
Pharmacokinetic Interaction ◽  
Compartment Model ◽  
Significant Degree ◽  
Volume Of Distribution ◽  
Gas Chromatography Mass Spectrometry ◽  
Effect Compartment ◽  
Drug Concentrations ◽  
Time Courses ◽  
Elimination Clearance ◽  
The Individual

Background The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil. Methods Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term. Results The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol. Conclusions Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.

scholarly journals Population Pharmacokinetics and Pharmacodynamic Implementation of Meropenem in Critically Ill Pediatric Patients

2020 ◽  
Author(s):  
Jumpei Saito ◽  
Kensuke Shoji ◽  
Yusuke Oho ◽  
Hiroki Kato ◽  
Shotaro Matsumoto ◽  
...  
Keyword(s):  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Intensive Care ◽  
Volume Of Distribution ◽  
Dosing Regimen ◽  
Final Model ◽  
The Mean ◽  
Higher Doses ◽  
Volumes Of Distribution ◽  
Significant Covariates

This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03–14.6) years old and 8.9 (2.7–40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), of which three received extracorporeal membrane oxygenation. Renal function, systemic inflammatory response syndrome (SIRS) score, and the use of CRRT for central volumes of distribution (Vc) were identified as significant covariates. The mean clearance (CL), Vc, and peripheral volume of distribution (Vp) were 0.45 l/kg/h, 0.49 l/kg, and 0.34 l/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and Vc increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of 100% free time above the minimum inhibitory concentration, and higher doses (40–80 mg/kg/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary.

scholarly journals Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Yewei Chen ◽  
Qian Shen ◽  
Min Dong ◽  
Ye Xiong ◽  
Hong Xu ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Pediatric Patients ◽  
Volume Of Distribution ◽  
Therapeutic Effects ◽  
Dosing Regimen ◽  
Open Label ◽  
Steroid Dependent ◽  
Central Volume ◽  
Higher Doses ◽  
Steroid Dependent Nephrotic Syndrome

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but the relapse rate remained high and the dosing regimen varied widely. The objective of this study was to characterize rituximab pharmacokinetics (PK) in pediatric patients with FRNS/SDNS, and to investigate the differences in rituximab PK between patients with FRNS/SDNS and other disease populations.Methods: Fourteen pediatric patients received rituximab for FRNS/SDNS treatment were enrolled in a prospective, open-label, single-center PK study. A population PK model of rituximab was developed and validated, and PK parameters were derived for quantitative evaluation.Results: A two-compartment PK model best described the data. Body surface area was the most significant covariate for both central clearance (CL) and apparent central volume of distribution (V1). Patients with FRNS/SDNS exhibited a clinically relevant increase in rituximab CL compared to patient population with non-Hodgkin’s lymphoma (NHL).Conclusion: This pilot study indicated that higher doses or more frequent regimens of rituximab may be required for optimal therapeutic effects in patients with FRNS/SDNS. Further clinical studies with more patients are warranted to confirm this result.

Pharmacokinetics of MMB4 DMS in Rats, Rabbits, and Dogs Following a Single IV Administration

2013 ◽  
Vol 32 (4_suppl) ◽  
pp. 30S-37S ◽  
Author(s):  
S. Peter Hong ◽  
Seth T. Gibbs ◽  
Dean J. Kobs ◽  
Merrill R. Osheroff ◽  
Jerry D. Johnson ◽  
...  
Keyword(s):  
Half Life ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Sprague Dawley ◽  
Elimination Half Life ◽  
Sprague Dawley Rats ◽  
Elimination Half ◽  
Op Nerve Agents

Organophosphorus (OP) nerve agents pose tremendous threats to both military and civilian populations. The substance 1,1′-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) is being developed as a replacement for the currently fielded 2-pyridine aldoxime, or pralidoxime (2-PAM) as a treatment for OP nerve agent–induced toxicity. The present study characterized pharmacokinetic (PK) profiles of MMB4 in male and female Sprague-Dawley rats, New Zealand White rabbits, and beagle dogs given a single intravenous (IV) administration of MMB4 dimethanesulfonate (DMS) at 55, 25, and 15 mg/kg dose, respectively. The plasma MMB4 concentration versus time profiles were biphasic for all species tested and fit a 2-compartment model with first-order elimination. There were no overt sex-related differences in the calculated PK parameters. For the rat, rabbit, and dog, the average systemic exposure parameters predicted Cmax (µg/mL) and AUC∞ (µg·h/mL) were 273 and 71.0, 115 and 48.1, and 87.4 and 39.6; the average volume of distribution (mL/kg) values to the central and peripheral compartments were 207 and 143, 242 and 172, and 198 and 213; and the average elimination half-life (hour) and clearance (mL/h/kg) values were 0.18 and 778, 0.29 and 577, and 0.32 and 430, respectively, when the PK parameters for males and females were combined. The current study revealed a similarity in the volume of distribution to the central compartment for MMB4 among the 3 species tested while demonstrating species-related differences in the elimination half-life and clearance of MMB4.

EFFECT OF OESTRONE-PELLET IMPLANTATION ON PLASMA LEVELS OF PROLACTIN

1970 ◽  
Vol 64 (2) ◽  
pp. 265-272 ◽  
Author(s):  
A. A. van der Gugten ◽  
M. Sala ◽  
H. G. Kwa
Keyword(s):  
Plasma Levels ◽  
Male Rats ◽  
Mean Values ◽  
The Mean ◽  
Dose Levels ◽  
Higher Doses ◽  
Primary Break

ABSTRACT Eight female and eight male rats were castrated at the age of 8 to 10 weeks. Four spayed and four orchidectomized rats received one oestrone/cholesterol pellet (200 μg oestrone) on the day of operation (day 0), a second pellet on day 11 and a third on day 23. The remaining animals received four oestrone/cholesterol pellets at these times. The fluctuations in the prolactin levels in the circulation induced by the oestrogen challenges in these animals were followed during 31 days by radioimmunoassays performed on days 3, 7, 9, 14, 15, 17, 23, 24, 25, 28 and 31. The results suggested that the homoeostatic mechanism regulating plasma levels of prolactin was capable of withstanding the three time-spaced oestrogen challenges only in the spayed animals receiving the lower doses of oestrogen, since it allowed the mean values of the prolactin levels to remain fairly constant during the first 4 weeks. The levels in this group rose to much higher levels only on day 31. The higher doses of oestrone in the spayed rats and both dose levels of oestrone in the orchidectomized animals apparently resulted in a primary break-down of the homoeostatic mechanism, since the prolactin levels in the animals of these groups rose to much higher levels either on day 7 or on day 9. This was followed by a period during which the prolactin levels appeared to be more or less under control, until a second and probably definitive failure of the homoeostatic mechanism allowed the mean levels to rise sharply again.

Remimazolam: A Novel Option for Procedural Sedation in High Risk Patients

2021 ◽  
pp. 089719002110273
Author(s):  
Megan M. Pantos ◽  
Daniel R. Kennedy ◽  
Eric C. Nemec
Keyword(s):  
Drug Interactions ◽  
The Elderly ◽  
Volume Of Distribution ◽  
Procedural Sedation ◽  
Dose Titration ◽  
Onset Of Action ◽  
Elimination Half ◽  
Risk Patients ◽  
Require Dose ◽  
Drug Review

Purpose: The purpose of this drug review was to explore the safety and efficacy of the newly approved benzodiazepine, remimazolam, in order to evaluate its place in therapy. Summary: Remimazolam has a faster onset of action and recovery time than midazolam when given as single IV doses. Additionally, it has no known CYP450 interactions that would contribute to drug-drug interactions. Patients with severe hepatic impairment may require dose titration as well as the elderly who should be closely monitored. Although remimazolam vials should be protected from light and must be reconstituted immediately before use, the reconstituted vial may be stored for later use at room temperature for up to 8 hours. Remimazolam is more expensive than current options used in practice, as such individual institutional formulary and provider preference will require review to see if its advantages are worth the additional cost and to determine its place in therapy. Conclusion: Remimazolam is a novel option when choosing a benzodiazepine for procedural sedation that has pharmacokinetic and pharmacodynamic advantages when compared to other commonly prescribed sedatives. Remimazolam has proved superior to midazolam when analyzing drug-drug interactions, onset, and time to alertness. Remimazolam also has a shorter elimination half-life and decreased volume of distribution when compared to midazolam.

scholarly journals Biological Effect of Different Spinach Extracts in Comparison with the Individual Components of the Phytocomplex

Foods ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 382
Author(s):  
Laura Arru ◽  
Francesca Mussi ◽  
Luca Forti ◽  
Annamaria Buschini
Keyword(s):  
Antioxidant Defense ◽  
Extraction Methods ◽  
Oxidizing Agent ◽  
Endogenous Reactive Oxygen Species ◽  
Dependent Activity ◽  
Main Components ◽  
The Individual ◽  
Dose Dependent ◽  
Higher Doses ◽  
Oxidative Insult

The Mediterranean-style diet is rich in fruit and vegetables and has a great impact on the prevention of major chronic diseases, such as cardiovascular diseases and cancer. In this work we investigated the ability of spinach extracts obtained by different extraction methods and of the single main components of the phytocomplex, alone or mixed, to modulate proliferation, antioxidant defense, and genotoxicity of HT29 human colorectal cells. Spinach extracts show dose-dependent activity, increasing the level of intracellular endogenous reactive oxygen species (ROS) when tested at higher doses. In the presence of oxidative stress, the activity is related to the oxidizing agent involved (H2O2 or menadione) and by the extraction method. The single components of the phytocomplex, alone or mixed, do not alter the intracellular endogenous level of ROS but again, in the presence of an oxidative insult, the modulation of antioxidant defense depends on the oxidizing agent used. The application of the phytocomplex extracts seem to be more effective than the application of the single phytocomplex components.

Chronopharmacology of β-Adrenoceptor-Blocking Drugs: Pharmacokinetic and Pharmacodynamic Studies in Rats

1983 ◽  
Vol 2 (6) ◽  
pp. 347-358 ◽  
Author(s):  
B. Lemmer ◽  
K. Bathe ◽  
P. H. Lang ◽  
G. Neumann ◽  
H. Winkler
Keyword(s):  
Treatment Time ◽  
Human Subjects ◽  
Temporal Variations ◽  
Male Rats ◽  
Pharmacokinetic Parameters ◽  
Nonspecific Effects ◽  
Elimination Half ◽  
Receptor Blockers ◽  
Β Receptor ◽  
Kinetics Of

Specific and nonspecific effects and the pharmacokinetic behavior of β-adrenoceptor-blocking drugs of different Iipophilicity (atenolol, bupranolol, carazolol, metoprolol, ox-prenolol, practolol, propranolol, sotalol) were investigated in L-D-synchronized male rats as a function of treatment time. The studies revealed that pharmacodynamic effects on heart rate, cardiac noradrenaline turnover, and motor activity as well as pharmacokinetic parameters of racemic mixtures of β-receptor blockers display temporal variations with more pronounced pharmacological effects and shorter elimination half-lives in the dark span. Studies with the isomers of bupranolol and practolol indicate no stereospecificity in the central depressant effect; the kinetic behavior of, for example, propranolol, however, exhibits stereospecificity. The results demonstrate the importance of circadian rhythms in modifying the effects and kinetics of drugs. These findings may have therapeutic implication in human subjects.

Effect of chronic intraperitoneal aminoguanidine on memory and expression of Bcl-2 family genes in diabetic rats

2016 ◽  
Vol 94 (6) ◽  
pp. 669-675 ◽  
Author(s):  
Mohsen Alipour ◽  
Fatemeh Adineh ◽  
Hossein Mosatafavi ◽  
Azam Aminabadi ◽  
Hananeh Monirinasab ◽  
...  
Keyword(s):  
Diabetic Rats ◽  
Male Rats ◽  
Cognitive Tasks ◽  
Negative Effects ◽  
Gene Expressions ◽  
Family Gene ◽  
Higher Doses ◽  
With Memory ◽  
Hippocampal Apoptosis

Long-term hyperglycemia associates with memory defects via hippocampal cells damaging. The aim of the present study was to examine the effect of 1 month of i.p. injections of AG on passive avoidance learning (PAL) and hippocampal apoptosis in rat. Eighty male rats were divided into 10 groups: control, nondiabetics and STZ-induced diabetics treated with AG (50, 100, 200, and 400 mg/kg, i.p.). PAL and the Bcl-2 family gene expressions were determined. Diabetes resulted in memory and Bcl-2 family gene expression deficits. AG (50 and 100 mg/kg) significantly improved the learning and Bcl-2, Bcl-xl, Bax, and Bak impairment in diabetic rats. However, negative effects were indicated by higher doses of the drug (200 and 400 mg/kg). Present study suggests that 1 month of i.p. injections of lower doses of AG, may improve the impaired cognitive tasks in STZ-induced diabetic rats possibly by modulating Bcl-2 family gene expressions.

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