Pharmacokinetics enzyme kinetics

BRADLEY A. SAVILLE is an Associate Professor of Chemical Engineering at i the University of Toronto. He received his B.Sc. and Ph.D. in chemical engi-neering at the University of Alberta. He is the author or co-author of over 25 research articles on enzyme kinetics, pharmacokinetics, heterogeneous reactions in biological systems, and reactors for immobilized enzymes. He is a member, of the Chemical Institute of Canada, the Canadian Society of Chemical Engineering, and Professional Engineers Ontario. 

Tracy, T.S. (2003) Atypical enzyme kinetics their effect on in vitro-in vivo pharmacokinetic predictions and drug interactions. Current Drug Metabolism, 4 (5), 341-346. 

Chemical clastogenesis and mutagenesis both involve a complex series of processes, including pharmacokinetic mechanisms (uptake, transport, diffusion, excretion), metabolic activation and inactivation, production of DNA lesions and their incomplete repair or misrepair, and steps leading to the subsequent expression of mutations in surviving cells or individuals (Thble 7.1). Each of the steps in these processes might conceivably involve first order kinetics at low doses (e.g., diffusion, MichaeUs-Menten enzyme kinetics) and hence be linear. In principle, therefore, the overall process edso might be linear and without threshold. 

The first two sections of Chapter 5 give a practical introduction to dynamic models and their numerical solution. In addition to some classical methods, an efficient procedure is presented for solving systems of stiff differential equations frequently encountered in chemistry and biology. Sensitivity analysis of dynamic models and their reduction based on quasy-steady-state approximation are discussed. The second central problem of this chapter is estimating parameters in ordinary differential equations. An efficient short-cut method designed specifically for PC s is presented and applied to parameter estimation, numerical deconvolution and input determination. Application examples concern enzyme kinetics and pharmacokinetic compartmental modelling. 

The sulfation of phenol and the glucuronidation of its hydroquinone metabolite were measured in human liver cytosols and microsomes, respectively. The rate of phenol sulfation varied between 0.31 and 0.92 nmol/mg protein/min this is slightly higher than the rate for mice (0.46) and lower than that for rats (1.20). The rate of hydroquinone glucuronidation was between 0.10 and 0.28 mnol/mg protein/min, slightly higher than that for rats (0.08) and lower than that for mice (0.22). These enzyme-kinetic data were subsequently used to simulate phenol metabolism in mice, rats and humans in vivo, using a com-partmental pharmacokinetic model with benzene as phenol precursor (Seaton et al., 1995). 

Many early PBPK modeling efforts were based on the Simusolv software, and support for this seems not readily available at the present time. More recently the ACSL and Berkeley Madonna (University of California, Berkley, CA) have become more widely used. In addition to these computer software packages, Haddad et al. [35] demonstrated the application of a spreadsheet program to support a PBPK model, and Trent University (Peterborough, Ontario, Canada, updated 2003) made available a spreadsheet program to run PBPK models. Further there are several computer-assisted applications, several as freeware, to perform pharmacokinetic analyses and interpret in vitro enzyme kinetic data (see Chapter 3). 

Because identification of a saturable process occurs only for low extraction ratio compounds (i.e., CL, etaboiism = /uCLint), the relationship between classical enzyme kinetics and pharmacokinetics is revealed ... 

This pathway is discussed in Section 7.5 Pharmacokinetics. However, we first need to discuss enzymes and enzyme kinetics, which we wit) do in Section 7.2. Check the CD-ROM and the web for future updates on metabolic reaction,... 

The mathematics of pharmacokinetics strongly resembles, and arises from, the mathematics of chemical kinetics, enzyme kinetics, and radioisotope (tracer) kinetics. Table 2.1 shows how, over the years, the mathematical theory of pharmacokinetics and that of its older siblings has been substantiated by experimental work. In fact, substantiation of a particular kinetic theory often... 

Alcohol dehydrogenase is a cytoplasmic enzyme mainly found in the liver, but also in the stomach. The enzyme accomplishes the first step of ethanol metabolism, oxidation to acetaldehyde, which is further metabolized by aldehyde dehydrogenase. Quantitatively, the oxidation of ethanol is more or less independent of the blood concentration and constant with time, i.e. it follows zero-order kinetics (pharmacokinetics). On average, a 70-kg person oxidizes about 10 ml of ethanol per hour. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

PBPK and classical pharmacokinetic models both have valid applications in lead risk assessment. Both approaches can incorporate capacity-limited or nonlinear kinetic behavior in parameter estimates. An advantage of classical pharmacokinetic models is that, because the kinetic characteristics of the compartments of which they are composed are not constrained, a best possible fit to empirical data can be arrived at by varying the values of the parameters (O Flaherty 1987). However, such models are not readily extrapolated to other species because the parameters do not have precise physiological correlates. Compartmental models developed to date also do not simulate changes in bone metabolism, tissue volumes, blood flow rates, and enzyme activities associated with pregnancy, adverse nutritional states, aging, or osteoporotic diseases. Therefore, extrapolation of classical compartmental model simulations... 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

Factors analogous to those affecting gut absorption also can affect drug distribution and excretion. Any transporters or metabolizing enzymes can be taxed to capacity—which clearly would make the kinetic process nonlinear (see Linear versus Nonlinear Pharmacokinetics ). In order to have linear pharmacokinetics, all components (distribution, metabolism, filtration, active secretion, and active reabsorption) must be reasonably approximated by first-order kinetics for the valid design of controlled release delivery systems. 

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