Pharmacokinetics zero-order

Design of a controUed release dosage form requires sufficient knowledge of both the desired therapy to specify a target plasma level and the pharmacokinetics. The desired dmg input rate from a zero order system may be calculated by ... 

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. 

Occluded applications Composition relatively invariant in use System size (area) predetermined Specific site prescribed for application Application technique highly reproducible Delivery is sustained Generally operate at unit drug activity, at least operate at steady activity Delivery is zero-order Serum levels related to product efficacy Bioequivalency based on pharmacokinetic (blood level) endpoint Unavoidable local tissue levels consequential only to system toxicity Individual dose interruptable Whole system removed when spent... 

C(t) modeled according to two-compartment model with zero-order and first-order absorption Pharmacokinetic/pharmacodynamic relationship modeled using Hill model with first-order absorption. Modeled parameters matched experimental parameters when bicompartmental model with zero-order input was used. Linear PKs, anticlockwise hysteresis loop established for all doses studied. Apomorphine and growth hormone concentration predicted with good accuracy... 

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 ... 

The proper dose of ketoprofen for an optimized zero-order model to obtain the desired drug level pattern to remain in the therapeutic range for 12 h (twice-a-day formulation) was estimated from drug pharmacokinetic parameters [6] by conventional equations [3] on the basis of a one-compartment open model and was found to be 1 lOmg. 

The concept of clearance is useful in pharmacokinetics because clearance is usually constant over a wide range of concentrations, provided that ehmination processes are not saturated. Saturation of biotransformation and excretory processes may occur in overdose and toxic okinetic effects should be considered. If a constant fraction of drug is eliminated per unit time, the elimination follows first-order kinetics. However, if a constant amount of drug is eliminated per unit time, the elimination is described by zero-order kinetics. Some drugs, for example, ethanol, exhibit zero-order kinetics at normal or non-intoxicating concentrations. However, for any drug that exhibits first-order kinetics at therapeutic or nontoxic concentrations, once the mechanisms for elimination become saturated, the kinetics become zero order and clearance becomes variable.3... 

K0 is now the zero-order rate constant and is expressed in terms of mass/time. In an active carrier-mediated transport process following zero-order kinetics, the rate of drug transport is always equal to K once the system is fully loaded or saturated. At subsaturation levels, the rate is initially first order as the carriers become loaded with the toxicant, but at concentrations normally encountered in pharmacokinetics, the rate becomes constant. Thus, as dose increases, the rate of transport does not increase in proportion to dose as it does with the fractional rate constant seen in first-order process. This is illustrated in the Table 6.1 where it is assumed that the first-order rate constant is 0.1 (10% per minute) and the zero-order rate is 10 mg/min. 

In contrast to noncompartmental analysis, in compartmental analysis a decision on the number of compartments must be made. For mAbs, the standard compartment model is illustrated in Fig. 3.11. It comprises two compartments, the central and peripheral compartment, with volumes VI and V2, respectively. Both compartments exchange antibody molecules with specific first-order rate constants. The input into (if IV infusion) and elimination from the central compartment are zero-order and first-order processes, respectively. Hence, this disposition model characterizes linear pharmacokinetics. For each compartment a differential equation describing the change in antibody amount per time can be established. For... 

The state-of-the-art approach to controlled release opioid therapy is to provide formulations which exhibit zero order pharmacokinetics and have minimal peak to trough fluctuation in opioid levels with repeated dosing. This zero order release provides very slow opioid absorption, and a generally flat serum concentration curve over time. A flat serum concentration is generally considered to be advantageous because it would in effect mimic a steady-state level where efficacy is provided but side effects common to opioid analgesics are minimized. 

The biexponential rate equation associated with this model was fitted to the experimental data using a nonlinear least squares procedure. Pharmacokinetic constants for the two-compartment model were calculated by standard methods. The fraction amount absorbed as a function of time was estimated by the Loo-Riegelman method using the macroscopic rate constants calculated from the intravenous data. The slope of the linear part of the Loo-Riegelman plot combined with the total amount absorbed (quantitated by depletion analysis of the saturated donor solution) was used to calculate the zero-order rate constant for buccal permeability. 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

Polymer-based systems offer numerous advantages, such as biocompatibility, biodegradability, and ability to incorporate functional groups for attachment of drugs. Drugs can be incorporated into the polymer matrix or in the cavity created by the polymeric architecture, from which the drug molecule can be released with an element of temporal control, and controlled pharmacokinetic profile with almost zero-order release achievable. 

Fig. 9. Semilogarithmic plots of plasma concentrations versus time for 3 doses of salicylate administered to the same subject, illustrating capacity-limited elimination. At low plasma concentrations, parallel straight lines are obtained from which the first-order elimination rate constant can be estimated. As long as concentrations remain sufficiently high to saturate the process, elimination follows zero-order kinetics (C. A. M. van Ginneken et al., J. Pharmacokinet. Biopharm., 1974,2, 395-415).

Many biochemistry laboratories no longer undertake routine measurement of the plasma concentration for most anticonvulsant drugs because plasma concentrations are insufficiently stable to serve as a useful guide to change of dose. The exception is phenytoin, where a small increase in dose may lead to a disproportionate rise in the plasma drug concentration (see zero-order pharmacokinetics, p. 99) and plasma monitoring is essential. With other drugs the dose is increased to the maximum tolerated level and, if seizures continue, it is replaced by another. 

Pharmacokinetics. Heparin is poorly absorbed from the gastrointestinal tract and is given i.v. or S.C. once in the blood its effect is immediate. Heparin binds to several plasma proteins and to sites on endothelial cells it is also taken up by cells of the reticuloendothelial system and some is cleared by the kidney. Due to these factors, elimination of heparin from the plasma appears to involve a combination of zero-order and first-order processes, the effect of which is that the plasma biological effect alters disproportionately with dose, being 60 min after 75 units per kg and 150 min after 400 units per kg. 

P6-8b (Pharmacokinetics) Tarzlon is a liquid antibiotic that is taken orally to treat infections of the spleen. It is effective only if it can maintain a concentration in the blood-stream (based on volume of bo(fy fluid) above 0.4 mg per dm of body fluid. Ideally, a concentration of l.Omg/dm in the blood would like to be realized. However, if the concentration in the blood exceeds 1.5 mg/dm, harmful side effects can occur. Once the Tarzlon reaches the stomach it can proceed in two pathways, both of which are first order (1) It can be absorbed into the bloodstream through the stomach walls (2) it can pass out through the gastrointestirral tract and not be absorbed into the blood. Both these processes are first order in Tarzlon concentration in the stomach. Once in the bloodstream, Tarzlon attacks bacterial cells and is subsequently degraded by a zero-order process. Tarzlon can also be removed from the blood and excreted in urine through a first-order process within the kidneys. In the stomach ... 

Landgren, B. Aedo, A. Johannisson, E. Cekan, S. Pharmacokinetic studies with a vaginal delivery system releasing levonorgestrel at a near zero order rate for one year. Contraception 1994, 49, 139-150. 

E. Pharmacokinetic and pharmacodynamic investigations with vaginal devices releasing levonorgestrel at a constant, near zero order rate. Contraception 1982, 26, 567-585. 

The coupling of the principles of controlled release from a zero-order rate device and long-term physiological pharmacokinetic modeling Is a unique research concept and will be used In Investigational systems where such drug delivery characteristics help elucidate physiological rate mechanisms. 

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