scholarly journals Elimination of fast variables in stochastic nonlinear kinetics

2020 ◽  
Vol 22 (36) ◽  
pp. 20801-20814
Author(s):  
Gabriel Morgado ◽  
Bogdan Nowakowski ◽  
Annie Lemarchand
Keyword(s):  
Nonlinear Kinetics ◽  
Elimination Of Fast Variables

The usually discarded intermediate Z significantly enhances Y fluctuations making the interpretation of FCS experiments based on reduced mechanisms delicate.

A new assay for diaphorase activity in reagent formulations, based on the reduction of thiazolyl blue.

1979 ◽  
Vol 25 (12) ◽  
pp. 2040-2042 ◽  
Author(s):  
R S Boethling ◽  
T L Weaver
Keyword(s):  
Nonlinear Kinetics ◽  
Tetrazolium Bromide ◽  
Diaphorase Activity ◽  
Blue Tetrazolium ◽  
Maximum Absorbance ◽  
Thiazolyl Blue Tetrazolium Bromide ◽  
Assay Procedure ◽  
Thiazolyl Blue Tetrazolium

Abstract This new assay procedure for diaphorase eliminates problems of high blank rates and nonlinear kinetics associated with other methods. The dye thiazolyl blue tetrazolium bromide is reduced in the presence of NADH and diaphorase to yield a colored formazan, which as maximum absorbance at 560 nm.

Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus Macaques

2004 ◽  
Vol 23 (3) ◽  
pp. 179-189 ◽  
Author(s):  
Sandhya Ramanathan-Girish ◽  
Paul Catz ◽  
Moire R. Creek ◽  
Benjamin Wu ◽  
David Thomas ◽  
...  
Keyword(s):  
Oral Dose ◽  
Oral Administration ◽  
Antimalarial Drug ◽  
Dose Range ◽  
Plasmodium Species ◽  
Repeat Dose ◽  
Nonlinear Kinetics ◽  
Dose Administration ◽  
Blood Concentrations ◽  
Cynomolgus Macaques

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats ( n = 4 /sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved Cmax after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and Cmax values following single oral dose administration were not dose proportional; the Cmax value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. MonodesethylAQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding Cmax values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism ofAQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

scholarly journals Incorporating Nonlinear Kinetics to Improve the Predictive Performance of Population Pharmacokinetic Models for Ciclosporin in Adult Renal Transplant Recipients: A Comparison of Modelling Strategies

2020 ◽  
Author(s):  
Jun-Jun Mao ◽  
Zheng Jiao ◽  
Xiao-Yan Qiu ◽  
Ming Zhang ◽  
Ming-Kang Zhong
Keyword(s):  
Renal Transplant ◽  
Predictive Performance ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Inhibitory Effects ◽  
Nonlinear Kinetics ◽  
Nonlinear Properties ◽  
Modelling Strategies

AbstractAimCiclosporin (CsA) has been shown to follow nonlinear pharmacokinetics in renal transplant recipients who received Neoral-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population pharmacokinetic (popPK) analysis. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability.MethodsA total of 2969 CsA whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulae on model predictability. Prediction-based and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models.ResultsModel predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theoretical relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance over that of the other three compartmental models. The saturated binding of CsA to erythrocytes, and auto-inhibition that arose from the inhibitory effects of CsA on CYP3A4/P-gp and CsA-prednisolone drug interaction may have contributed to the nonlinearity.ConclusionsIncorporating nonlinear properties are likely to be a promising approach for improving CsA model predictability. However, CsA nonlinear kinetics resources need further investigation. Until then, Michaelis-Menten empirical model can be used for CsA dose adjustments.What is already known about this subjectCsA in renal transplant recipients receiving Neoral-based triple immunosuppressive therapy followed nonlinear pharmacokinetics.Nonlinearity is rarely incorporated into CsA population pharmacokinetic (popPK) modelling processes.What this study addsFour popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based compartmental kinetic models and empirical formulae, as well as the effect of nonlinearity on CsA model predictability.Based on the four models, incorporating nonlinear properties is likely to be a promising approach for improving CsA model predictability.Saturated distribution into red blood cells, and auto-inhibition that arose from the inhibitory effects of CsA on CYP3A4/P-gp and CsA-prednisolone drug interaction may be the main sources of CsA PK nonlinearity.Principal Investigator statementThe authors confirm that the Principal Investigator for this paper is Zheng Jiao and that he had direct clinical responsibility for patients.

scholarly journals Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks

2019 ◽  
Vol 9 (5) ◽  
pp. 20190021 ◽  
Author(s):  
Alexander Erlich ◽  
Gareth A. Nye ◽  
Paul Brownbill ◽  
Oliver E. Jensen ◽  
Igor L. Chernyavsky
Keyword(s):  
Maternal Blood ◽  
Physiological Parameter ◽  
Nonlinear Kinetics ◽  
Tissue Metabolism ◽  
Capillary Networks ◽  
Solute Uptake ◽  
Terminal Villi ◽  
Parameter Values ◽  
The Impact ◽  
Villous Tissue

The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime.

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