New linear plots for the separate estimation of Michaelis—Menten parameters

Fajszi, Cs.; Endrényi, László

doi:10.1016/0014-5793(74)80734-9

Cited by 17 publications

(5 citation statements)

References 11 publications

(2 reference statements)

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“…The Hill coefficient (n) was also calculated by using the plot outlined by Fajszi & Endrenyi (1974) as adapted by J. Jeffery (personal communication), which does not depend on an estimation of V. Pairs of values of substrate concentrations (S, and S,) were taken so that the ratio SJS, was a constant arbitrary factor a. The values of the velocity (v, and vb) corresponding to the substrate concentrations were read from the graph of the normailzed results of velocity against substrate concentration in the range of S, = 4.0 to 0.6 mM.…”

Section: Resultsmentioning

confidence: 99%

A Kinetic Study of a Solubilized Chitin Synthetase Preparation from Coprinus cinereus

Rousset-Hall

Gooday

1975

Journal of General Microbiology

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S U M M A R YThe solubilized chitin synthetase preparation from the stipes of Coprinus cinereus is activated by its substrate, UDP-N-acetylglucosamine, and by carbohydrates, in particular N-acetylglucosamine, diacetylchitobiose and glucose. Analysis of the results of variation in enzyme activity with UDP-GlcNAc concentration by several methods suggested that this substrate is an allosteric activator, with Hill coefficients close to 2 and 4 at concentrations above and below 0.1 mM respectively, and an [S],., value of 0.9 mM. N-acetylglucosamine lessened but did not abolish the sigmoidal shape of the velocity-substrate concentration plot. The chitin synthetase was inhibited by adenine and uridine nucleotides, and uridine diphosphate was a powerful competitive inhibitor. The enzyme peparation also contained a nucleoside diphosphatase activity and the implications of the removal of the inhibitory UDP formed by the chitin synthetase are considered.

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Section: Resultsmentioning

confidence: 99%

A Kinetic Study of a Solubilized Chitin Synthetase Preparation from Coprinus cinereus

Rousset-Hall

Gooday

1975

Journal of General Microbiology

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“…In a recent study [2] we reported that multiple inhibitions of (first-order) Michaelis-Menten kinetic systems with noncompetitive, mutually nonexclusive inhibitors in single substrate reactions may be described by: (19) By using the general principles described above, we can develop a simple short-hand method for deriving equations for multiple inhibitions by mutually nonexclusive inhibitors in first-order and higher-order kinetic systems. To illustrate this (A:), 2 / I = ( 0 1 ' W * , .…”

Section: First Ordermentioning

confidence: 99%

Generalized Equations for the Analysis of Inhibitions of Michaelis-Menten and Higher-Order Kinetic Systems with Two or More Mutually Exclusive and Nonexclusive Inhibitors

Chou

Talalay

2005

European Journal of Biochemistry

369

262

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The following simple and generalized equation not involving kinetic constants for substrates (K,) or inhibitors (K,) describes the summation of the effects of two mutually exclusive and reversible inhibitors on enzyme systems obeying Michaelis-Menten kinetics :where,ii and,X( = 1 -,ii) are the fractional velocity and the fractional inhibition of the reaction, respectively, and I,, is the concentration of the inhibitor (I) that is required to produce 507; inhibition (i.e. the median effect). More specifically, (fJ1 and V;)2 are the fractional velocities i n the presence ofinhibitors I , and I,, respectively, and (f;)]. the fractional velocity in the simultaneous presence of both inhibitors.For mutually nonexclusive reversible inhibitors that follow Michaelis-Menten kinetics, the relationship becomes :Similar relationships apply to situations involving more than two inhibitors, for which generalized equations are given in the text. The above relationships express summation of inhibitory effects, irrespective of the number of substrates, the number of inhibitors, the type of reversibie inhibition (competitive, noncompetitive, or uncompetitive), or the kinetic mechanisms (sequential or ping-pong) of the enzyme reaction under consideration. These concepts have been extended to higher-order (Hill-type) systems in which each reversible inhibitor has more than one binding site. If such inhibitors are mutually exclusive:where m is a Hill-type coefficient, assumed to be the same for each inhibitor. If the inhibitors, I, and I,, are mutually nonexclusive, this relationship becomes :It may be seen that (for higher-order mutually exclusive and nonexclusive inhibitors), when (jJl,2 = 0.5, the above relationships are equal to unity, and hence require no knowledge of the magnitude of the values of m for each inhibitor. The above relations at (jJl, = 0.5 describe I,,-isobolograms (curves for isoeffective combinations of inhibitors).The above-described relationships lend themselves to simple graphical representations, directly applicable to + 12] will be concave upward, and will intersect ihe plot for the morc potent of the two inhibitors.

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“…In the development of the structural PK model, the concentration-time data were fitted to one-and two-compartment models with linear and nonlinear clearance (CL nonlinear ), and the suitability of the models was assessed. Nonlinear elimination pathways were explored by incorporating CL described by Michaelis-Menten kinetics 14 (Eq. 1):…”

Section: Base Modelmentioning

confidence: 99%

Population pharmacokinetics of the anti-PD-1 antibody camrelizumab in patients with multiple tumor types and model-informed dosing strategy

Wang

Sheng

et al. 2020

Acta Pharmacol Sin

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Objective: Camrelizumab, a programmed cell death 1 (PD-1) inhibitor, has been approved for the treatment of relapsed or refractory classical Hodgkin lymphoma. The aim of this study was to perform a population pharmacokinetics (PK) analysis of camrelizumab to quantify the impact of patient characteristics on PK and to investigate the appropriateness of flat dose in the dosing regimen. Methods: A total of 3298 camrelizumab concentrations from 133 patients from four studies were analyzed using nonlinear mixed effects modeling. Covariate model building was conducted using stepwise forward addition and backward elimination. Monte Carlo simulation was conducted to compare exposures of 200 mg and 3 mg/kg every 2-week regimens. Results: The PK of camrelizumab were adequately described by a two-compartment model with parallel linear and nonlinear clearances. Baseline albumin had significant effects on linear clearance, and weight had effects on inter-compartmental clearance. Moreover, 200 mg and 3 mg/kg regimens provide similar exposure distributions with no advantage to either dosing approach. Conclusion: Population PK analysis provided an integrated evaluation of the impact of albumin and weight on the PK of camrelizumab. It also provided evidence that neither the flat-dose nor the weight-based dose regimen was advantageous over the other for most patients with tumors.

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New linear plots for the separate estimation of Michaelis—Menten parameters

Cited by 17 publications

References 11 publications

A Kinetic Study of a Solubilized Chitin Synthetase Preparation from Coprinus cinereus

A Kinetic Study of a Solubilized Chitin Synthetase Preparation from Coprinus cinereus

Generalized Equations for the Analysis of Inhibitions of Michaelis-Menten and Higher-Order Kinetic Systems with Two or More Mutually Exclusive and Nonexclusive Inhibitors

Population pharmacokinetics of the anti-PD-1 antibody camrelizumab in patients with multiple tumor types and model-informed dosing strategy

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