Nonlinear Kinetic Behavior Research Articles

Linear and Nonlinear Isotherm, Kinetic, and Thermodynamic Behavior of Safranine T Adsorption Using Porous Geopolymer Prepared from Coal Fly Ash Wastes

Linear and Nonlinear Isotherm, Kinetic, and Thermodynamic Behavior of Safranine T Adsorption Using Porous Geopolymer Prepared from Coal Fly Ash Wastes

Relationship between spatially heterogeneous reaction dynamics and photochemical kinetics in single crystals of anthracene derivatives.

Understanding physicochemical property changes based on reaction kinetics is required to design materials exhibiting desired functions at arbitrary timings. In this work, we investigated the photodimerization of anthracene derivatives in single crystals. Single crystals of 9-cyanoanthracene (9CA) and 9-anthraldehyde (9AA) exhibited reaction front propagation on the optical length scale, while 9-methylanthracene and 9-acetylanthracene crystals underwent spatially homogeneous conversion. Moreover, the sigmoidal behavior in the absorbance change associated with the reaction was much pronounced in the case of 9CA and 9AA and correlated with the observation of heterogeneous reaction progress. A kinetic analysis based on the Finke-Watzky model showed that the effective quantum yield of the photochemical reaction changes by more than an order of magnitude during the course of the reaction in 9CA and 9AA. Both the reaction front propagation and nonlinear kinetic behavior could be rationalized in terms of the difference in the cooperativity of the reactions. We propose a plausible mechanism for the heterogeneous reaction progress in single crystals that depends on the magnitude of the conformational change required for reaction. Our results provide useful information to understand the connection between photochemical reaction progress in the crystalline phase and the dynamic changes in the physicochemical properties.

Linear and nonlinear isotherm, kinetic and thermodynamic behavior of benzene adsorption using sodium dodecyl sulfate functionalized magnetic nanoparticle adsorbent

Linear and nonlinear isotherm, kinetic and thermodynamic behavior of benzene adsorption using sodium dodecyl sulfate functionalized magnetic nanoparticle adsorbent

Linear and nonlinear isotherm, kinetic and thermodynamic behavior of methyl orange adsorption using modulated Al2O3@UiO-66 via acetic acid

The kinetic, isotherm and thermodynamic parameters of adsorption were investigated to obtain the optimum conditions of adsorption. Error analysis methods such as RMSE and χ2 were used to determine the best kinetic equation and isotherm. From the adsorption kinetics study, the linear pseudo second order model showed an effective adsorption mechanism and the most suitable adsorption isotherm was the linear Langmuir isotherm model. Based on the linear Langmuir isotherm model, the maximum adsorption capacities of UiO-66 and Al(M100)@UiO-66 were 233.65 and 268.82 mg/g, respectively. The results showed that the linear method was better suited to take into account the adsorption parameters than the nonlinear method. The resulting R2 values of other kinetic models, namely Intraparticle Diffusion and Elovich, were still below that of the linear pseudo second order model and the resulting R2 values of other isotherm models, namely Temkin, Dubinin-Radushkevich, and Scatchard, were still below that of the linear Langmuir isotherm model. The adsorption thermodynamic study showed that the adsorption process was exothermic and spontaneous. Other operational parameters such as pH, ionic strength and adsorbent dose were also discussed. Al(M100)@UiO-66 can be regenerated up to four times using a diluted HCI solution.

Transport and Retention of Molybdenum(VI) in Soils: Kinetic Modeling

Core Ideas Mo(VI) sorption was kinetically controlled and highly nonlinear in two different soils. Mo(VI) retention mechanism in Windsor sand was different from Webster loam. Rate‐limited processes greatly influenced Mo(VI) transport in soils. Mo(VI) transport was well described using a second‐order model. Understanding the mechanisms and kinetics controlling the retention and transport of molybdenum [Mo(VI)] is a prerequisite in the effort to evaluate environmental risk of groundwater contamination. In this study, kinetic batch and miscible‐displacement experiments were performed to investigate Mo(VI) adsorption–desorption and transport behaviors on a neutral soil (Webster loam) and a slightly acidic soil (Windsor sand). Batch results indicated that adsorption of Mo(VI) was kinetically controlled and highly nonlinear in both soils. The Mo(VI) maximum adsorption and kinetic rate for acidic Windsor sand was much higher than for neutral Webster loam. Mo(VI) breakthrough curves (BTCs) were asymmetrical and exhibited extensive tailing with incomplete recovery in the effluent: these features demonstrate that rate‐limited or non‐equilibrium process influenced Mo(VI) transport behavior. To better understand the controls on the nonlinear kinetic behavior of Mo transport in these soils, a second‐order (SO) model which accounts for equilibrium, reversible, and irreversible retention mechanisms was used to describe Mo(VI) retention and transport in soils. Based on optimized and predictive modeling results, a fully reversible equilibrium‐kinetic SO model successfully described the time‐dependent Mo(VI) sorption for Webster loam. However, for Windsor sand, which exhibited strong affinity and low mobility for Mo(VI), an additional consecutive irreversible reaction phase was necessary to describe Mo(VI) retention and transport with time.

Reconstitution of CYP3A4 active site through assembly of ligand interactions as a grid-template: Solving the modes of the metabolism and inhibition

A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules. The template shape was determined mainly through reciprocal comparisons of simulation results with available experiment data mainly on recombinant CYP3A4-mediated reactions of polyaromatic hydrocarbon (PAH) ligands. Through the applications of various PAH and non-PAH ligands on the template, couple region-specific interactions including mechanisms to facilitate ligand movement from the initial site to a place near heme-oxygen and to trigger of catalyses are envisioned. These are very effective tools to verify candidates of CYP3A4 ligands as the good or poor substrates. The bi-molecule binding idea also explains so called “cooperative bindings with activator/effector” as interactions with non-identical trigger molecules on this CYP3A4-template system, and also offers possible mechanisms of the non-linear kinetic behavior.

Nonlinear Kinetic Behavior in Constitutional Dynamic Reaction Networks.

Creating synthetic chemical systems which emulate the complexity observed in cells relies on exploiting chemical networks exhibiting nonlinear kinetic behavior. While control over reaction complexity using synthetic gene regulatory networks and DNA nanotechnology has developed greatly, little control exists over small molecule reaction networks. Toward this goal, we demonstrate a general framework for inducing nonlinear kinetic behavior in dynamic chemical networks based on molecules containing reversible chemical bonds. Specifically, this strategy relies on constituent species with differing thermodynamic stabilities that readily exchange components at rates that are faster than their formation rates. Such nonlinear networks (NLN) readily lead to sigmoidal kinetic profiles as a function of the relative thermodynamic stabilities of the constituent species. Furthermore, this behavior could be readily extended to more complex mixtures while maintaining nonlinearity. The generality of this method opens the possibility to generate nonlinear networks using a broad range of small molecule structures.

Reaction Mechanism of Aluminum-Particle-Air Detonation

Both in-tube and unconfined experimental evidence showed strong dependence of micrometric aluminum-air detonability on initial pressure and highly nonlinear behavior of abrupt deflagration-to-detonation transition, thus indicating dependence of the aluminum reaction mechanism of the detonation waves on chemical kinetics. On the other hand, the observed aluminum―air detonation manifested itself in a weak transverse wave structure, as revealed by the small-amplitude oscillation that rapidly degenerates behind the shock front in the pressure histories. This suggests a functional dependence that is weaker than the nonlinear Arrhenius kinetic behavior for the later aluminum combustion. Hence, a surface kinetic oxidation and diffusion hybrid reaction model with a degree of condensed detonation products was suggested, and the unsteady two-phase fluid dynamics modeling showed the success of the hybrid reaction model, capable of capturing both the kinetics-limited transient processes of detonation initiation, abrupt deflagration-to-detonation transition and detonation instability, and the diffusion-limited combustion of aluminum in the long reaction zone, supporting the weak transverse wave structure.

A two-dimensional mathematical model of non-linear dual-sorption of percutaneous drug absorption

BackgroundCertain drugs, for example scopolamine and timolol, show non-linear kinetic behavior during permeation process. This non-linear kinetic behavior is due to two mechanisms; the first mechanism being a simple dissolution producing mobile and freely diffusible molecules and the second being an adsorption process producing non-mobile molecules that do not participate in the diffusion process. When such a drug is applied on the skin surface, the concentration of the drug accumulated in the skin and the amount of the drug eliminated into the blood vessel depend on the value of a parameter, C, the donor concentration. The present paper studies the effect of the parameter value, C, when the region of the contact of the skin with drug, is a line segment on the skin surface. To confirm that dual-sorption process gives an explanation to non-linear kinetic behavior, the characteristic features that are used in one-dimensional models are (1) prolongation of half-life if the plot of flux versus time are straight lines soon after the vehicle removal, (2) the decrease in half-life with increase in donor concentration. This paper introduces another feature as a characteristic to confirm that dual-sorption model gives an explanation to the non-linear kinetic behavior of the drug. This new feature is "the prolongation of half-life is not a necessary feature if the plots of drug flux versus time is a non-linear curve, soon after the vehicle removal".MethodsFrom biological point of view, a drug absorption model is said to be nonlinear if the sorption isotherm is non-linear. When a model is non-linear the relationship between lag-time and donor concentration is non-linear and the lag time decreases with increase in donor concentration. A two-dimensional dual-sorption model is developed for percutaneous absorption of a drug, which shows non-linear kinetic behavior in the permeation process. This model may be used when the diffusion of the drug in the direction parallel to the skin surface must be examined, as well as in the direction into the skin, examined in one-dimensional models. The dual-sorption model is an initial/boundary value problem which consists of (1) one non-linear, two-dimensional, second-order parabolic equation, (2) boundary conditions, (3) one initial condition. Note that, the number of boundary conditions are, six and four, respectively, if the permeation process under consideration is, during the application of the vehicle and during the removal of the vehicle. Adopting the approach of method of lines, the initial/boundary value problem is transformed into an initial-value problem, which consists of (1) a system of non-linear ordinary differential equations, (2) one initial condition. The system of non-linear ordinary differential equations contains time-dependent non-homogeneous terms, if the permeation process under consideration is, during the application of the vehicle. To solve this initial-value problem, an eight-stage sequential algorithm which is second-order accurate, and requires only tri-diagonal solvers, is developed.ResultsSimulation of the numerical methods described is carried out with various values of the parameter C. The illustrations are given in the form of figures. The concentration profiles are viewed as parabolas along the mesh lines parallel to x-axis or y-axis. The flow rates in different subregions of the skin-region are studied. The shapes of the concentration profiles are examined before and after the steady-state concentration is reached. The concentration reaches steady-state when the flux reaches the steady state. The plots of flux versus time and cumulative amount of drug eliminated into the receptor cell versus time are given.ConclusionBased on the various values of the parameter, C, conclusions are drawn about (1) flow rate of the drug in different regions of the skin, (2) shape of the concentration profiles, (3) the time required to reach the steady-state value of the concentration, (4) concentration of the drug in different regions of the skin, when steady-state value of the concentration is reached, (5) the time required to reach the steady-state value of the flux, (6) time required to reach the steady-state value of the concentration of the drug, (7) half-life of the concentration of the drug and (8) lag-time.A comparison, between this two-dimensional model and the one-dimensional non-linear dual-sorption model that exists in the literature, is done based on (1) the shape of the concentration profiles at various time levels, (2) the time required to reach the steady-state value of the concentration, (3) lag-time and (4) half-life.

Molecular cloning and characterization of a thermostable carboxylesterase from an archaeon, Sulfolobus shibatae DSM5389: Non-linear kinetic behavior of a hormone-sensitive lipase family enzyme

A gene coding for an esterase ( SshEstI, 915 bp in length) of the thermoacidophilic archaeon Sulfolobus shibatae DSM5389 was cloned, sequenced, and overexpressed in Escherichia coli JM109 cells as a soluble, catalytically active protein. The deduced amino acid sequence of SshEstI was consistent with a protein containing 305 amino acid residues with a molecular mass of 33 kDa. Sequence comparison studies indicated that SshEstI could be a member of the hormone-sensitive lipase family, in that it had the highest sequence similarity to esterases from Sulfolobus solfataricus (90% identity) and Archaeoglobus fulgidus (42%) and a lipase from Pseudomonas sp. B11-1 (38%). The recombinant enzyme was highly thermostable and retained more than 70% of its initial activity after incubation at 90°C and pH 7.0 for 30 min. The recombinant enzyme catalyzed the hydrolysis of p-nitrophenyl ( p-NP) esters with C 2–C 16 acyl chains but not the hydrolysis of triacylglycerides such as tributyrin and triolein. The enzymatic hydrolysis of p-NP acetate proceeded in a linear manner with time, whereas that of p-NP esters with acyl chains of C 5 or longer showed a biphasic profile, where a rapid release of p-nitrophenol (∼3 min) was followed by a slow, sustained release. These non-linear kinetics may be explained in terms of a very slow, presteady-state burst phenomenon of p-nitrophenol release or a hysteretic behavior of SshEstI with these substrates.

Molecular Cloning and Characterization of a Thermostable Carboxylesterase from an Archaeon, Sulfolobus shibatae DSM5389: Non-Linear Kinetic Behavior of a Hormone-Sensitive Lipase Family Enzyme

A gene coding for an esterase (SshEstI, 915 bp in length) of the thermoacidophilic archaeon Sulfolobus shibatae DSM5389 was cloned, sequenced, and overexpressed in Escherichia coli JM109 cells as a soluble, catalytically active protein. The deduced amino acid sequence of SshEstI was consistent with a protein containing 305 amino acid residues with a molecular mass of 33 kDa. Sequence comparison studies indicated that SshEstI could be a member of the hormone-sensitive lipase family, in that it had the highest sequence similarity to esterases from Sulfolobus solfataricus (90% identity) and Archaeoglobus fulgidus (42%) and a lipase from Pseudomonas sp. B11-1 (38%). The recombinant enzyme was highly thermostable and retained more than 70% of its initial activity after incubation at 90°C and pH 7.0 for 30 min. The recombinant enzyme catalyzed the hydrolysis of p-nitrophenyl (p-NP) esters with C2–C16 acyl chains but not the hydrolysis of triacylglycerides such as tributyrin and triolein. The enzymatic hydrolysis of p-NP acetate proceeded in a linear manner with time, whereas that of p-NP esters with acyl chains of C5 or longer showed a biphasic profile, where a rapid release of p-nitrophenol (∼3 min) was followed by a slow, sustained release. These non-linear kinetics may be explained in terms of a very slow, presteady-state burst phenomenon of p-nitrophenol release or a hysteretic behavior of SshEstI with these substrates.

Stochastic resonance in catalytic reduction of NO with CO on Pt(100)

This paper presents a stochastic resonance occurring in a chemical reaction Pt(100)/NO+CO. The results were from numerical simulation of the nonlinear kinetic behavior of a three-variable reaction model obtained from the law of mass actions. The model exhibits a special region in the bifurcation scheme, where a stable node coexists with a stable limit cycle. When one of the control parameters is perturbed by a weak, low frequency periodic signal riding on a suitable external noisy background, transitions between the steady state and oscillatory state may become regular unexpectedly, and signal to noise ratio is thus enhanced at the signal frequency in the Fourier transform power spectrum of the time series output. That refers to stochastic resonance, in which the noise may play a constructive role in the detection of weak signals. The findings may suggest a new method to develop chemical sensitive devices in the field of applications. The paper also discusses the conditions of occurrence of stochastic resonance, and studies the laws it follows.

Polybitoxins: a group of phospholipases A 2 from the venom of the neotropical social wasp paulistinha ( Polybia paulista)

The neotropical wasp Polybia paulista is very aggressive and endemic in south-east Brazil, where it frequently causes stinging accidents. By using gel filtration on Sephadex G-200, followed by ion-exchange chromatography on DEAE-Cellulose under a pH gradient, a group of four toxins (designated as polybitoxins-I, II, III and IV) presenting phospholipase A 2 (PLA 2) activities was purified. These toxins are dimeric with mol. wts ranging from 115,000 to 132,000 and formed by different subunits. The four toxins contain very high sugar contents attached to their molecules (22–43% w/w) and presented different values of pH optimum from 7.8 to 9.0; when dissociated, only residual catalytic activities were maintained. The catalytic activities of polybitoxins (from 18 to 771 μmoles/mg per minute) are lower than that of PLA 2 from Apis mellifera venom and hornetin from Vespa basalis. The polybitoxins presented a non-linear steady-state kinetic behavior for the hydrolysis of phosphatidylcholine at pH 7.9, compatible with the negative co-operativity phenomena. All of the polybitoxins were very potent direct hemolysins, especially the polybitoxins-III and IV, which are as potent as the lethal toxin from V. basalis and hornetin from Vespa flavitarsus, respectively; polybitoxin-IV presented hemolytic action 20 times higher than that of PLA 2 from A. mellifera, 17 times higher than that of neutral PLA 2 from Naja nigricolis and about 37 times higher than that of cardiotoxin from Naja naja atra venom.

Reactivity and gas-phase acidity determinations of small peptide ions consisting of 11 to 14 amino acid residues

Small peptides ions consisting of a comparable number of amino acid residues but varying in composition and sequence were allowed to undergo gas-phase deprotonation reactions. These multiply protonated ions were generated by electrospray ionization and analyzed in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The peptides studied contain 11-14 amino acid residues and included adrenocorticotropic hormone (ACTH) fragment (11-24), fibrinopeptide B (human), gastrin I fragment (1-13) (human), renin substrate tetra-decapeptide (horse), somatostatin, substance P and tyrosine protein kinase. Rate constants were determined for the deprotonation reactions of the peptide ions with a series of reference compounds of known gas-phase basicities ranging from 190.0 to 232.6 kcal mol-1. From these values, apparent gas-phase acidities (GAapp) were assigned to [M + nH]n+ (n > or = 2), of each peptide. All of the multiply charged peptide ions were sequentially deprotonated to the +1 charge state by ion-molecule reactions. The GAapps ranged from 193.3 kcal mol-1 (for [M + 4H]4+ of renin substrate, the ion most readily deprotonated) to > 232.6 kcal mol-1 (for [M + 2H]2+ of ACTH (11-24), the ion most difficult to deprotonate). The proximity of intrinsically basic sites (and therefore potential protonation sites) has an effect on the observed deprotonation rates. Ions experiencing Coulomb repulsion resulting from adjacent protonation sites often show more facile deprotonation. However, the intrinsic basicity of a protonation site also plays a role in determining the case of deprotonation. As a result, some lower charge state peptide ions deprotonate more readily than other peptides with higher charges but with more basic protonation sites. In addition, conformation and the influence of intramolecular hydrogen bonding may affect the reactivity of some peptide ions. Also observed was non-linear kinetic behavior that indicates multiple isomers at certain charge states for some peptides, e.g. [M + nH]n+, (n = 2 and 3) for ACTH 11-24 and [M + 3H]3+ for somatostatin.

Nonlinear Pharmacokinetics of Mibefradil in the Dog

The pharmacokinetics of mibefradil in the dog was evaluated in this study. Single intravenous (1 mg/kg) and three oral doses (1, 3, 6 mg/kg) of mibefradil were administered to three dogs according to a randomized complete block design, where dogs were blocks and treatments randomly assigned to each block. Systemic plasma clearance, volume of distribution at steady-state and half-life after intravenous administration were as follows: ClS ) 18.4 ± 1.2 mL/min/kg, VSS ) 9.7 ± 3.8 L/kg, and T1/2 ) 9.5 ± 3.4 h. Oral plasma clearance decreased with an increase in dose, from 101.8 ± 18.8 mL/min/kg at 1 mg/kg to 21.7 ± 4.3 mL/min/kg at a 6 mg/kg dose (p< 0.05). Half-life values did not change significantly with an increase in oral dose in all the animals studied (10.6 ± 1.5 h at 1 mg/kg vs 13.4 ± 3.5 h at 6 mg/kg). Dose-normalized AUC ratios between the oral and intravenous treatments increased from 0.18 ± 0.03 at 1 mg/kg to 0.87 ± 0.21 at a 6 mg/kg dose (p < 0.05). The nonlinear kinetic behavior of mibefradil is consistent with an increase in gut absorption and/or reduction in elimination after higher oral doses. Although both dogs and humans exhibit nonlinear pharmacokinetics after oral administration, there are substantial differences in the clearance and volume of distribution values between these two species. Even though these differences can, in part, be accounted for by the difference in plasma protein binding, the use of the dog as an animal model for human mibefradil pharmacokinetics needs to be qualified.

Nonlinear Chemical Dynamics: Oscillations, Patterns, and Chaos

Chemical reactions with nonlinear kinetic behavior can give rise to a remarkable set of spatiotemporal phenomena. These include periodic and chaotic changes in concentration, traveling waves of chemical reactivity, and stationary spatial (Turing) patterns. Although chemists were initially skeptical of the existence and the relevance of these phenomena, much progress has been made in the past two decades in characterizing, designing, modeling, and understanding them. Several nonlinear dynamical phenomena in chemical systems provide simpler analogues of behaviors found in biological systems.

14] Combinatorial chemistry: A liquid-phase approach

The development of bioavailable organic compounds in a combinatorial format is obligatory for the advancement of combinatorial chemistry from a pharmaceutical standpoint. Ingrained early on in this quest for reaction methodologies, leading to “small molecule” libraries, was the need for simple product isolation, facile manipulation of the “portioning-mixing” technique, and the ability to drive a reaction to completion. Polymer-supported synthesis has emerged as one of the most important tools in research efforts focused on the construction of nonoligopeptide/nucleotide libraries. As promising as the “solid-phase” method in a combinatorial format seems, it has certain drawbacks. The most notable of these is the heterogeneous reaction conditions that can lead to some of the following potential problems: (1) nonlinear kinetic behavior, (2) unequal distribution and/or access to the chemical reaction, (3) solvation problems, and (4) pure synthetic problems, associated with solid-phase synthesis. Because of these potential limitations that solid-phase synthesis presents, alternative methodologies have been sought out from a combinatorial point of view. This chapter describes a liquid-phase methodology and shows its utility in the synthesis of a peptide and sulfonamide library. This chapter has shown how a technology termed “liquid-phase combinatorial synthesis” can simplify and further accelerate the combinatorial chemical process. This methodology combines the advantages that classic organic synthesis offers, in solution with those that solid-phase synthesis can provide. The findings here indicate that the reaction scope of liquid-phase combinatorial synthesis (LPCS) should be general. Its value to high-throughput screening assays could be of particular merit, since multimilligram quantities of each library member can be obtained.

Pharmacokinetics of N-Methyldiethanolamine Following Acute Cutaneous and Intravenous Dosing in the Rat

The pharmacokinetics and tissue distribution of N-methyldieth-anolamine (MDEA) were studied in the Fischer 344 rat after a single intravenous (50 or 500 mg/kg) or cutaneous dose (500 mg/kg for 6 or 72 h contact). Topically applied MDEA was well absorbed by both male and female rats (17–21% and 41–50% after 6 and 72 h contact, respectively), after apparently being first sequestered in the skin and later slowly released into the bloodstream. Distribution of MDEA was relatively uniform throughout the major organs, with the highest concentrations being in the liver and kidney. MDEA was substantially metabolized. Metabolism of MDEA could be saturated at high dosages since nonlinear kinetic behavior was observed in rats dosed intravenously with 500 mg/kg. The predominant excretion route for MDEA was in the urine. Urinary excretion of MDEA was slow, with an excretion half-life in excess of 30 h following cutaneous dosing. Metabolites constituted the major fraction in urine, indicating that metabolism plays an important role in MDEA elimination.

Functional characterization of the mitochondrial cytochrome b- c1 complex: Steady-state kinetics of the monomeric and dimeric forms

The QH 2:cytochrome c oxidoreductase activity of the isolated bovine heart cytochrome b- c 1 complex resolved into monomeric and dimeric form was titrated with three different inhibitors of electron transfer, antimycin, myxothiazol, and 5- n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). In all cases one inhibitor molecule per cytochrome c 1 was found necessary to block completely the activity of both molecular forms of the enzyme. The antimycin-sensitive cytochrome c reduction catalyzed by the b- c 1 complex was also studied as a function of increasing concentrations of either cytochrome c or quinol. Double-reciprocal plots of the activity of the monomeric enzyme were found linear either when the concentration of cytochrome c or of quinol derivatives, 2,3-dimetoxy-5-methyl-6-decyl-1,4-benzoquinol (DBH), and 2-methyl-3-undecyl-1,4-naphthoquinol (UNH), was changed. Cytochrome c reductase activity of the dimeric b- c 1 complex also showed a linear Lineweaver-Burk plot as a function of cytochrome c concentrations. In contrast to the monomeric enzyme, however, dimers of the b- c 1 complex express a clear nonlinear kinetic behavior toward quinol derivatives, with two apparent K m values differing approximately by one order of magnitude (about 3–4 and about 20–30 μ m). At saturating quinol concentrations the activity of the dimeric enzyme becomes two to three times higher than that of monomers. The nonlinear kinetic plots were found to be the same at different temperatures and different cytochrome c concentrations. The data suggest that although the monomer of the b- c 1 complex appears to be the functional unit of the enzyme, the dimer is more active. A regulatory role of the dimerization process resulting in an increase of the electrons flux through the enzyme is postulated.

Model-Independent Steady-State Plasma Level Predictions in Autonomic Nonlinear Pharmacokinetics I: Derivation and Theoretical Analysis

Current drug level predictions in nonlinear pharmacokinetics are based on specific pharmacokinetic models in contrast to the model-independent (structureless), dose-linearity, and superposition principles used in linear pharmacokinetics. Such model-dependent methods may not provide reliable predictions due to their inherent nonuniqueness, computational complexity, and often unrealistic kinetic assumptions. Some novel model-independent methods for predicting the steady-state drug levels of extravascular, intravenous bolus, and intravenous infusion administrations are presented that should overcome such disadvantages. The methods only assume an autonomic nonlinear kinetic behavior, which implies that following an intravenous bolus administration the derivatives of the drug concentration-time profile at arbitrary drug levels are independent of the dose given. Such a kinetic behavior is found for any nonlinear pharmacokinetic system when the rate of change of the drug level following an intravenous bolus administrations depends only on the drug level, i.e., dC/dt = −q(C), where q can be any function dependent only on C and time-invariant kinetic parameters. The basic approach presented represents a novel alternative which avoids the very difficult and often impractical task of identifying and incorporating the numerous kinetic parameters and processes responsible for the observed drug concentration data into a useful pharmacokinetic model. The focus in the kinetic analysis is instead on two much simpler processes: (a) fitting empirical functions to estimate the mean drug disposition behavior of the subject or population and (b) testing the validity of the assumptions involved.