Absorption, distribution, metabolism linear

The Basic Concept of the QSAR Technique. The QSAR technique has been widely employed in modeling biological activities as well as ADME/Tox (absorption, distribution, metabolism, excretion, toxicity) properties. This approach was first introduced by Flansch et al. in 1963, on the basis of linear... 

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

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. 

PK modeling can take the form of relatively simple models that treat the body as one or two compartments. The compartments have no precise physiologic meaning but provide sites into which a chemical can be distributed and from which a chemical can be excreted. Transport rates into (absorption and redistribution) and out of (excretion) these compartments can simulate the buildup of chemical concentration, achievement of a steady state (uptake and elimination rates are balanced), and washout of a chemical from tissues. The one- and two-compartment models typically use first-order linear rate constants for chemical disposition. That means that such processes as absorption, hepatic metabolism, and renal excretion are assumed to be directly related to chemical concentration without the possibility of saturation. Such models constitute the classical approach to PK analysis of therapeutic drugs (Dvorchik and Vesell 1976) and have also been used in selected cases for environmental chemicals (such as hydrazine, dioxins and methyl mercury) (Stem 1997 Lorber and Phillips 2002). As described below, these models can be used to relate biomonitoring results to exposure dose under some circumstances. 

The pharmacokinetics of dofetihde are linear after single oral doses of 2-10 micrograms/kg (24,35) and repeated doses of 1.0-2.5 mg/day (25). Dofetilide is well absorbed (abont 90%) after oral administration (24,35,36). Its absorption is relatively slow and peak concentrations are not reached for 1-2.5 hours absorption is slower after food. It is a low clearance drug, with a clearance rate of abont 6 ml/minnte/kg, and has a volume of distribution of about 31/kg (23,36). It is mostly excreted unchanged by the kidneys, with a half-life of about 8 hours. Its clearance is therefore roughly proportional to creatinine clearance, particularly at high rates of clearance. A small proportion is metabolized in the liver by CYP3A4 to inactive metabohtes (37). 

Rodent and human studies have shown that MTBE is rapidly absorbed following inhalation exposure. In addition, rodent studies have shown rapid distribution of MTBE after oral and intraperitoneal exposure. Dermal absorption occurs more slowly. Evidence supports metabolic transformation of MTBE by P450 enzymes to the parent alcohol, t-butyl alcohol (TBA), and formaldehyde in rodents and humans. Further oxidative metabolism of TBA seems to be slow, and glucuronidation is a major competing pathway. Formaldehyde metabolism to formate is very rapid. The toxicokinetic parameters of MTBE and TBA depend on the dose and route of administration although they appear to be linear following inhalation exposures up to 50 ppm. 

Conceptual models of percutaneous absorption which are rigidly adherent to general solutions of Pick s equation are not always applicable to in vivo conditions, primarily because such models may not always be physiologically relevant. Linear kinetic models describing percutaneous absorption in terms of mathematical compartments that have approximate physical or anatomical correlates have been proposed. In these models, the various relevant events, including cutaneous metabolism, considered to be important in the overall process of skin absorption are characterized by first-order rate constants. The rate constants associated with diffusional events in the skin are assumed to be proportional to mass transfer parameters. Constants associated with the systemic distribution and elimination processes are estimated from pharmacokinetic parameters derived from plasma concentration-time profiles obtained following intravenous administration of the penetrant. 

Linear (or first-order) kinetics refers to the situation where the rate of some process is proportional to the amount or concentration of drug raised to the power of one (the first power, hence the name first-order kinetics). This is equivalent to stating that the rate is equal to the amount or concentration of drug multiplied by a constant (a linear function, hence linear kinetics). All the PK models described in this chapter have assumed linear elimination (metabolism and excretion) kinetics. All distribution processes have been taken to follow linear kinetics or to be instantaneous (completed quickly). Absorption processes have been taken to be instantaneous (completed quickly), follow linear first-order kinetics, or follow zero-order kinetics. Thus out of these processes, only zero-order absorption represents a nonlinear process that is not completed in too short of a time period to matter. This lone example of nonlinear kinetics in the standard PK models represents a special case since nonlinear absorption is relatively easy to handle mathematically. Inclusion of any other type of nonlinear kinetic process in a PK model makes it impossible to write the... 

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