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Изучение биоэквивалентности является одним из ключевых исследований, необходимых для регистрации воспроизведенного лекарственного препарата для перорального при-ема. Дизайн указанного типа исследования обусловливается многими факторами, в том числе линейностью фармакокинетики действующего вещества. При регистрации нескольких дозировок препарата именно от данного свойства будет зависеть выбор дозы в исследовании биоэквивалентности. На примере атазанавира и валацикловира рассмотрены регуляторные требования к планированию исследований биоэквивалентности препаратов, обладающих нелинейной фармакокинетикой. Анализ исследований биоэквивалентности согласно данным государственного реестра лекарственных средств (ГРЛС), а также опубликованных открытых данных исследований биоэквивалентности выявил различия как в изучаемых дозировках, так и в количестве проведенных исследований. При планировании и оценке исследований биоэквивалентности (БЭ) препаратов с нелинейной фармакокинетикой следует принимать во внимание характеристики действующего вещества, все доступные литературные данные, международный опыт и современные регуляторные требования.

Fenarimol (FNL), an organic chlorinated fungicide, is widely used in agriculture for protection from fungal spores and fungi. Despite being an endocrine disruptor, no toxicokinetic data is reported for this fungicide. In the present work, we determined the plasma protein binding, metabolic pathways and toxicokinetics of FNL in rats.

Activated carbon obtained from ayous sawdust, Cucurbitaceae (egussi) peelings and the mixture of the two were studied for the adsorption of phenacetin. Characterisation of activated carbon by SEM and XRD analysis shows that the mixture of precursors combine the properties of activated carbon obtained separately. The well-knownbatch sorption models– Langmuir (one and two sites), Freudlich, Tempkin, Elovich, Langmuir-Freudlich, Redlich Peterson, Radke-Prausnitz, Fritz Shlunder)—were tested with experimental data for the adsorption of phenacetin to estimate adsorption equilibrium parameters—rate constantsand adsorption capacities. The model with the best fit was identified from extensive statistical analysis of the results of nonlinear regression of the experimental data. Comparison of the statistical errors in parameter estimation between linear and non-linear isotherm models shows that transformation of non-linear isotherm equations to linear forms implicitly alter their error structure. The much smaller size of the various error indicators —Determination Coefficient, R2; Sum of Square Errors, SSE; Chi Test, χ2; Average Relative Errors, ARE—, calculated for the case of non linearization when compared to linearization, indicate the greater accuracy in the application of non linearization. The Langmuir model (one site) gave the best fit and thus the values of adsorption capacity for each activated carbon were calculated from it. Kinetic models show that weak and strong interactions are involved in the adsorption process and that the controlling mechanism may not be limited to intra particle diffusion. The lower value of the boundary layer thickness in the case of activated carbon obtained from the mixture, justified the higher adsorbed quantity of this activated carbon compared to those of activated carbon from each precursor.

Background and Objectives: The prediction of pharmacokinetics of monoclonal antibodies (mAbs) exhibiting non-linear pharmacokinetics in preclinical species to human is challenging, and very limited scientifc work has been published in this feld of research. Therefore, we have conducted an elaborate comparative assessment to determine the most reliable preclinical to clinical scaling strategy for mAbs with non-linear pharmacokinetics. Methods: We have compared three diferent scaling approaches to predict human pharmacokinetics from cynomolgus monkey. In the frst approach, cynomolgus monkey pharmacokinetic parameters estimated using a two-compartment model with parallel linear and non-linear elimination were allometrically scaled to simulate human pharmacokinetics. In the second approach, allometric exponents were integrated with a minimal physiologically based pharmacokinetic (mPBPK) model to translate human pharmacokinetics. In the third approach, we have employed a species time-invariant method, wherein a two-compartment model with parallel linear and non-linear elimination was used as a framework model for simulation of the human profle. Results: Human exposure parameters projected by an integrated allometric method were only within two fold for approximately 45–70% of predictions at diferent doses of fve mAbs evaluated, while approximately 70–80% of Cmax and AUC predictions by integrated mPBPK modelling as well as the species time-invariant method were within two-fold error. The average fold error for clearance predictions by the integrated mPBPK method was 1.10–1.45 fold, whilst for the species time-variant and integrated allometric methods, the average fold error was between 1.04 and 1.37 fold and 1.24 and 2.13 fold, respectively. Conclusions: Our fndings suggest that the species time-variant method and mPBPK proposed by us can be employed to reliably translate non-linear pharmacokinetics of mAbs from cynomolgus monkey to human.

International audience; Roscovitine (Seliciclib), a new protein kinase inhibitor, was administered orally to adult patients with cystic fibrosis for the first time in the ROSCO-CF trial, a dose-escalation, phase IIa, randomized, controlled trial. Extensive pharmacokinetic sampling was performed up to 12 h after the first oral dose. Roscovitine and its main metabolite M3 were quantified by liquid chromatography coupled with tandem mass spectrometry. The pharmacokinetics analyses were performed by non-linear mixed effects modelling. Monte Carlo simulations were performed to assess the impact of dose on the pharmacokinetics of oral roscovitine. Twenty-three patients received oral doses ranging from 200 to 800 mg of roscovitine and 138 data points were available for both roscovitine and M3 concentrations. The pharmacokinetics was best described by a two-compartment parent-metabolite model, with a complex saturable absorption process modelled as the sum of Gaussian inverse density functions. The Monte Carlo simulations showed a dose-dependent and saturable first-pass effect leading to pre-systemic formation of M3. The treatment with proton-pump inhibitors reduced the rate of absorption of oral roscovitine. The pharmacokinetics of oral roscovitine in adult patients with cystic fibrosis was non-linear and showed significant inter-individual variability. A repeat-dose study will be required to assess the inter-occasional variability of its pharmacokinetics.

Chito-protein was successfully synthesized from fish scale. The ability of a coagulant (chito-protein) prepared from fish scale (FSC) to carry out an effective removal of pollutants from food processing industry (vegetable oil industry wastewater, VOW) was evaluated at bench scale using a simulated jar test analysis. The coagulant was characterized via proximate analysis and instrumental analysis: Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The maximum kinetic parameters determined were recorded at K of 2x10-5L/mg.min, 1g, t1∕2= 50 min, R2= 0.9245 and pH of 2.Regression coefficient analysis (R2) was used to ascertain the accuracy of the fit to the postulated kinetic model. However, it was concluded that the second order kinetic model described the reaction most adequately. Removal efficiency of turbidity (87.21%) was obtained at optimum contact time of 30 min, pH 2, coagulant dosage of 1.5g and temperature of 323K. Kinetic study showed that Pseudo first order and pseudo second order models were the best two models in describing the coag-adsorptive kinetics of the coagulant. Similarly, the predicted kinetic data were adjured statistically significant using F- test and T-test.

Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine ( p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups ( p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former ( p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.

A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer's rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity over PDE6 that were hitherto unprecedented in the sildenafil scaffold. UK-371,800 (compound 8) was identified as a development candidate from this series that married sildenafil-like molecular properties with high selectivity over PDE6. Clinical data confirm that UK-371,800 has markedly superior human pharmacokinetics to a previously-described higher molecular weight achiral analogue in this template (compound 1).

This paper describes an approximation method for the estimation of effectiveness factors in porous catalysts that have reactions with non-linear kinetic models. The reaction rate expression is expressed as a combination of two asymptotic solutions based on a local concentration, leading to an approximate rate function containing four parameters. The effectiveness factors computed with the approximated rate are shown to be close to the values calculated from the real rate function for a variety of non-linear LHHW type models. The advantage of the approximate method is that a given set of four parameters, which can easily be calculated, uniquely identifies an effectiveness factor. This observation enables the construction of a table from which the effectiveness factor can be readily extracted during reactor simulation, thus resulting in a decrease in computational effort.

Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

There are many applications in pharmacokinetic described and modelled by linear or non-linear differential equation systems. These non-linarities can be considered in pharmacokinetic model parameters and the pharmacokinetics of drug action. The Euler’s- and Taylor’s expansion methods are applied for numerical solution pharmacokinetic equations. A fictitious exciting functions method makes possible numerical solution of this DE system with non-stationary matrices. The solutions of warfarin target-mediated drug disposition are presented as well.

Safety production in chemical plants is a high-priority task, especially as concerns reactions which can change mechanism suddenly under defined conditions, e.g. from a simple well-defined to an undesired autocatalytic reaction. An example of this kind, the reaction of chloronitrobenzene with alkaline alcohol, was investigated with the new adiabatic precision calorimeter ACTRON 5, designed with a safety concept. It is shown that the reaction can be interrupted safely under predicted conditions.

Objective To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. Methods A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. Results The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/ day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. Conclusions The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens.

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.

A computational algorithm is developed for the solution of mass and heat balance equations for highly-exothermic reactions described by complex reaction networks and non linear kinetics in a fluidized bed

The pharmacokinetics of oral and i.v. propafenone and its major metabolites have been investigated in 8 healthy subjects. The total body clearance of propafenone was 963 ml/min, the terminal half-life 198 min and its absolute bioavailability was 15.5%. The two active metabolites (5-hydroxypropafenone and N-depropylpropafenone) showed non-linear kinetics in that both the dose-corrected area under the serum concentration-time curve and the amount excreted in the urine were larger after oral dosing. This resulted in considerably higher serum concentrations of the metabolites despite comparable serum concentrations of the parent compound. Thus, the concentration-effect relationship in the same patient may differ after oral and intravenous doses if concentrations of the active metabolite(s) are not taken into consideration. Although the mechanism of the nonlinearity is not clear, the data indicate that it may be due to saturable biliary excretion of the metabolites.

Azole antifungals have different pharmacokinetic characteristics: complete oral absorption for Voriconazole, and to a lesser extent for fluconazole. The absorption of posaconazole and itraconazole increases with food intake. All of them have high tissue distribution with low plasma concentrations, especially low in the case of posaconazole and itraconazole. Posaconazole and itraconazole have high plasmatic protein binding and consequently both have a very low free fraction. Elimination of azole antifungals is through a metabolic pathway with CYP450 isoenzymes, and has a non linear pharmacokinetics with a high risk of interation with other drugs since azoles have the ability of CYP450 isoenzymes inhibition. Possibly the parameter that defines more precisely their efficacy is AUIC with an optimum value near 20, although cut-off values must be defined since some azoles may have difficulty to reach this value.

What is meant by non-linear pharmacokinetics? When the dose of a drug is increased, we expect that the concentration...

Recently, in the ref. Physica A \bfm{296} 405 (2001), a new one parameter deformation for the exponential function $\exp_{_{\{{\scriptstyle \kappa}\}}}(x)= (\sqrt{1+\kappa^2x^2}+\kappa x)^{1/\kappa}; \exp_{_{\{{\scriptstyle 0}\}}}(x)=\exp (x)$, which presents a power law asymptotic behaviour, has been proposed. The statistical distribution $f=Z^{-1}\exp_{_{\{{\scriptstyle \kappa}\}}}[-\beta(E-\mu)]$, has been obtained both as stable stationary state of a proper non linear kinetics and as the state which maximizes a new entropic form. In the present contribution, starting from the $\kappa$-algebra and after introducing the $\kappa$-analysis, we obtain the $\kappa$-exponential $\exp_{_{\{{\scriptstyle \kappa}\}}}(x)$ as the eigenstate of the $\kappa$-derivative and study its main mathematical properties., Comment: 5 pages including 2 figures. Paper presented in NEXT2001 Meeting

In the present effort we consider the most general non linear particle kinetics within the framework of the Fokker-Planck picture. We show that the kinetics imposes the form of the generalized entropy and subsequently we demonstrate the H-theorem. The particle statistical distribution is obtained, both as stationary solution of the non linear evolution equation and as the state which maximizes the generalized entropy. The present approach allows to treat the statistical distributions already known in the literature in a unifying scheme. As a working example we consider the kinetics, constructed by using the $\kappa$-exponential $\exp_{_{\{\kappa\}}}(x)= (\sqrt{1+\kappa^2x^2}+\kappa x)^{1/\kappa}$ recently proposed which reduces to the standard exponential as the deformation parameter $\kappa$ approaches to zero and presents the relevant power law asymptotic behaviour $\exp_{_{\{\kappa\}}}(x){\atop\stackrel\sim x\to \pm \infty}|2\kappa x|^{\pm 1/|\kappa|}$. The $\kappa$-kinetics obeys the H-theorem and in the case of Brownian particles, admits as stationary state the distribution $f=Z^{-1}\exp_{_{\{\kappa\}}}[-(\beta mv^2/2-\mu)]$ which can be obtained also by maximizing the entropy $S_{\kappa}=\int d^n v [ c(\kappa)f^{1+\kappa}+c(-\kappa)f^{1-\kappa}]$ with $c(\kappa)=-Z^{\kappa}/ [2\kappa(1+\kappa)]$ after properly constrained., Comment: To appear in Phys. Lett. A

In this book we have so far restricted ourselves to particular collective motions-electrostatic modes-and we have mainly considered Langmuir and ion-sound oscillations. However, for those collective modes we have tried to show as fully as possible what is known about their different non-linear interactions and non-linear kinetic processes. We have considered all that is known about all the interactions and relations between the various non-linearities. We want now to emphasise that the modes considered are representatives of many other modes which can occur in actual plasmas. For practical applications one needs therefore only to know the whole spectrum of the modes which may occur in a system and their interactions. Inclusion of a broad spectrum of modes will also broaden the spectrum of interactions, but not that of the kind of interactions-which we have considered in detail. The behavior of all other interactions can be formulated by complete analogy of those we have considered so far. However, there may be specific points in which these interactions may be different in some way from what we have considered earlier and in the present chapter we shall try to look at those points.

The pharmacokinetics of flecainide has been studied in 12 patients with ventricular arrhythmias, both after single administration and during chronic treatment. Both the half-life and the AUC were significantly increased during chronic treatment. This suggests that the kinetics of flecainide might be non-linear also in patients with normal kidney and liver function. The increase in plasma flecainide levels during chronic treatment could not be predicted, so close monitoring of its plasma levels is advisable.

Although aprindine (AP), an anti-arrhythmic drug, had been shown to follow a non-linear pharmacokinetics in human subjects with a very large inter-subject variability, the metabolic pathways contributing the non-linear pharmacokinetic disposition of AP have not been clarified yet. Pharmacokinetics of AP and its metabolites, p-OHAP, i-OHAP and DEAP, was studied in seven arrhythmic patients administering 20mg to 60mg of AP every 12 hour for 2 weeks, and was evaluated the non-linearity using a mixed effect model analysis. The partial formation clearances of i-OHAP and p-OHAP from AP showed AP dose dependency. Metabolic parameters for formation of metabolites, p-OHAP, i-OHAP and DEAP from AP were obtained using human and rat liver microsomes, and compared. Lower capacities and higher affinities of i-OHAP and p-OHAP formations shown in human microsomes reasonably described of the non-linearity of AP disposition in humans.

In order to evaluate the pharmacokinetic profile of the alcohol dehydrogenase inhibitor 4-methylpyrazole 4-MP, a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase-I study" was performed in healthy male volunteers at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4) and 100 mg.kg-1 (n = 3). In the 10 and 20 mg.kg-1 group, the elimination of 4-MP from the plasma followed non-linear kinetics with mean rates of concentration decline of 3.66 and 5.05 mumol.l-1.h-1, respectively. In the two highest dose groups, the elimination also appeared to be non-linear although the patterns were not followed long enough to confirm this. The mean rates of concentration decline at the higher doses were significantly increased, up to 14.9 mumol.l-1.h-1 at 100 mg.kg-1. The average renal clearance of 4-MP was low, 0.016 ml.min-1.kg-1, and only 3% of the administered dose was excreted unchanged in the urine, indicating metabolism as the major route of elimination. Because of the apparently unusual kinetics following single dose treatment, thorough multiple dose studies need to be carried out to determine a safe dosage regimen for 4-MP.

Three simple linear and three simple non-linear pharmacokinetic models are presented which incorporate the reversible metabolism that occurs between prednisone and prednisolone. Under steady-state conditions it is possible to not only distinguish between the linear and non-linear models but also to determine which particular model of each group applies to a given set of data. While the non-linear conversion of prednisolone to prednisone is important in explaining the pharmacokinetics of prednisone in all three non-linear models, the same is not true for prednisolone.

Tube-wall reactors are gaining importance for highly exothermic and fast chemical reactions because of their simple construction and improved temperature control. A generalized mathematical model of the non-isothermal annular tube-wall reactors for simultaneous catalytic reactions with mixed type non-linear reaction kinetics and volume change is developed. Numerical solutions of two-dimensional component transfer equations, heat transfer equation and fluid flow equation may be obtained with appropriate boundary conditions using a recently developed orthogonal collocation method for annular geometries. The model has been successfully applied to the tube-wall reactors for the Fischer-Tropsch Synthesis. Comparison between model predictions and previous experimental results is good. Les reacteurs a paroi tubulaire gagnent de l'importance pour les reactions chimiques et hautement exothermiques en raison de leur conception simple et d'un contrǒle ameliore de la temperature. On a mis au point un modele mathematique generalise du reacteur a paroi tubulaire annulaire non isotherme pour des reactions catalytiques simultanees avec une cinetique de reaction non lineaire du type melange et un changement de volume. Des solutions numeriques des equations de transfert de composants bidimensionnelles, de l'equation de transfert de chaleur et de l'equation de l'ecoulement peuvent ětre obtenues avec des conditions limites adequates en utilisant une methode de collocation orthogonale elaboree recemment pour les geometries annulaires. Ce modele a ete applique avec succes aux reacteurs a paroi tubulaire pour le procede Fischer-Tropsch. La comparaison entre les predictions du mdele et les resultats experimentaux anterieurs montre un bon accord.

Salivary excretion profiles of 5-fluorouracil (5-FU) were investigated following bolus intravenous administration at three dose levels (12.5, 25, and 50 mg/kg) in rats. Mandibular (M) and parotid (Pr) saliva samples were periodically collected separately via cannulas inserted into the ducts by stimulating salivation with pilocarpine infused intravenously. Simultaneously, salivary pH, flow rate, and protein concentration were determined.(1) Plasma and saliva 5-FU concentration decreased bi-exponentially with time. A relatively scattered relationship but a statistically significant correlation was found between each of the saliva concentrations and plasma 5-FU concentration (p

Intravenous zero order infusions were administered to New Zealand white rabbits. In a pilot study using one rabbit, prednisone and prednisolone clearance values increased with increase in either prednisone or prednisolone infusion rates. In the second study, prednisone was infused until both prednisone and prednisolone achieved steady-state concentrations. In the third study, prednisone was infused until only prednisone achieved steady-state concentrations. The results of the three experiments support the use of a non-linear reversible metabolism model to describe the pharmacokinetic relationship between prednisone and prednisolone.

The non-linear dynamics of a heterogeneous reactor is considered by extending the treatment of Weinberg and Ergen . The new features present in the heterogeneous case are discussed, and results and conclusions are obtained for comparison with experiments performed on the Chatillon reactor.

If a partially segregated system is considered as a number of particles with an interdiffusion of chemical components according to an opportune exchange factor, it is possible to calculate the mean conversion of reactions with non linear kinetics by integrating the mass balances for each particle. From this point of view research was carried out on normal second-order reactions, 2A → products, with or without volume change, autocatalytic reactions and bimolecular reactions A + B → products, with reactants fed in separately. In a CSTR, segregation has a favourable effect on the mean conversion in the first two cases and an unfavourable effect in the latter two. Moreover, it was shown that the size of the exchange factor may be correlated to parameters characteristic of the turbulence within the tank.

We have so far considered only ‘linear’ systems, i.e. enzymes that give hyperbolic plots of v against [S] and linear plots of 1/v against 1/[S]. Although many enzymes do fall into this category, others clearly deviate from linearity within the normally studied ranges of substrate concentration, and these include many enzymes occupying strategically important positions in metabolism. The non-linearity can frequently be rationalized teleologically in terms of desirable control characteristics.

Research regarding parameters suitable for reporting on the activity of enzymatic systems responsible for ethanol metabolism is of obvious interest in medico-legal practice. Blood ethanol concentration-time curves, following oral administration of ethanol, have been developed for ethylic and non-ethylic subjects. This study has confirmed the non-linear kinetics of ethanol elimination; however, existing non-linear models appear to be inadequate for usual medico-legal practice, because of their complexity. We observed three phases during the elimination of ethanol. The first order terminal phase is characterized by its half-life. This parameter seems adequate as a basis for determining the activity of enzyme systems responsible for the metabolism of ethanol.

The following report analyzes equations of motion for somewhat idealized circulating-fuel reactor that have been previously discussed, specifically the assumptions that the instantaneous power density is constant along the length of the fuel tubes, that the excess radioactivity depends only upon the average fuel temperature, and that the fuel temperature at the inlet is kept constant.

Pretreatment of rats with phenobarbital, but not with 3-methylcholanthrene, induces liver microsomal styrene monooxygenase. Under these conditions the kinetic profile is not linear and can be divided into 2 distinct curves. Evidence is presented indicating that the combined treatment with phenobarbital and CoCl2 destroy the high affinity enzyme, suggesting that the native cytochrome is less sensitive to the action of CoCl2.

The drug disposition after intravenous injection of sulfamono-methoxine(SMM: 10,50 and 100mg/kg) in pig was studied by analysis of plasma and urine data. Blood and urine were serially collected for 12-36 hrs and for 72 hrs after dosing, respectively. SMM and its metabolites were determined by the modified method of Bratton & Marschall and a fluorometric method. The time course of drug concentration in plasma appeared to be linear on semilog paper after injection of 10mg/kg of SMM. On the other hand, after 100mg/kg, the decline of plasma concentration was slow at early stage and afterward,tended to curve inward and with further time,appeared to be linear,suggesting that the disposition of a high dose of SMM was by non-linear kinetics with capacity limited elimination. The non-linear drug disposition was observed 3/5 of pigs after 50mg/kg. About 80% of the total SMM excreted was recovered as acetyl deriva-tives(AcSMM) from urine at each SMM dose. Renal clearance of AcSMM at each urine sampling time was constant throughout the experiment at 10mg/kg;but at 50 and 100mg/kg, different values were obtained according to the experimental stage,that is, low in the early stage and high afterwards. While much AcSMM was observed in plasma after the drug injection, the ratio of appearance of AcSMM and that of SMM was not different with the administered doses(about 1/2). This fact showed that the saturation of renal clearance capacity of AcSMM may be the causal factor for the non-linear kinetics of SMM at a high dose.