Kinetics first-order elimination

Once a semilog plasma concentration versus time plot begins to follow simple first-order elimination kinetics, the remaining AUC can be calculated in one step using Eq. (45). 

First-order elimination kinetics are described by the equation 1... 

In other words, for elimination processes that follow first order kinetics tm is a constant, characteristic of the drug and the biological system. Consequently, for drugs that exhibit first order elimination kinetics both and ke and t]/2 are used as indicators of the rate of elimination of a drug from the system. Half-lives are normally quoted in the literature and kel values are calculated as required using equation (8.5). 

Expressions similar to Equation (8.30) may be obtained for drugs that do not exhibit first order absorption and elimination characteristics by substituting the appropriate kinetic relationships in Equation (8.29). For example, for a drug that exhibits zero order absorption and first order elimination kinetics, Equation (8.29) becomes ... 

Renal clearance (CIR) represents the volume of blood cleared by the kidney per unit time and is a constant for drugs with first-order elimination kinetics. Total body clearance equals renal plus nonrenal clearance. An important relationship is Cl = k x Vd. 

A patient was given a 160-mg dose of a drug IV, and 80 mg was eliminated during the first 120 minutes. If the drug follows first-order elimination kinetics, how much of the drug will remain 6 hours after its administration ... 

The superposition principle, which forms the basis of all multiple-dose models in this section, is true only as long as all elimination processes follow first-order (linear) elimination kinetics. Since the assumption of first-order elimination kinetics has already been made for all the previous single-dose models that are being combined by superposition, the application of the superposition principle does not add any new model assumptions. 

Linear pharmacokinetics applies that is, the rate process obeys passive diffusion and first-order elimination kinetics (please review first-order process). 

The permanganate oxidation of oxalic acid has been studied exhaustively and has been reviewed by Ladbury and Cullis . It is characterised by an induction period and a sigmoid dependence of rate upon time. Addition of manganous ions eliminates the induction period and produces first-order decay kinetics . Addition of fluoride ions, however, practically eliminates reaction . ... 

To predict oral plasma concentration-time profiles, the rate of drug absorption (Eq. (53)) needs to be related to intravenous kinetics. For example, in the case of the one-compartment model with first-order elimination, the rate of plasma concentration change is estimated as... 

The elimination of [i C]triethanolamine from the blood of mice administered 1.0 mg/kg bw intravenously showed first-order biphasic kinetics with a rapid (0.58-h half-life) and a slow phase (10.2-h half-life). The slow phase half-lives for elimination of triethanolamine in mice after dermal exposure to 1000 and 2000 mg/kg bw in acetone were 9.7 h and 18.6 h. Skin absorption rates (as blood concentration-time curves) after dermal application of aqueous and neat [I CJtriethanolamine to mouse skin (2000 mg/kg bw, enclosed by a glass ring) showed no significant change with the use of water as the vehicle (Waechter Rick, 1988, cited in Knaak et al, 1997). 

The NH acidities of some sterically hindered ureas, namely the ureido esters (93), have been reported.81 The kinetics and mechanism of the alkaline hydrolysis of urea and sodium cyanate, NaCNO, have been studied at a number of temperatures.82 Urea hydrolysis follows an irreversible first-order consecutive reaction path. Tetrahedral intermediates are not involved and an elimination-addition mechanism operates. Sodium cyanate follows irreversible pseudo-first-order kinetics. The decomposition of the carcinogen /V-mcthyl-/V-nitrosourca (19) was dealt with earlier.19 The pyrolysis of /V-acctylurca goes by a unimolecular first-order elimination reaction.83... 

A low-temperature study in superacid media of mono-, di-, and tri-protonated thiourea has been earned out.302 The experimental results were confirmed by theoretical calculations. Monoprotonation occurs at sulfur and, whereas the mono- and di-protonated forms are thermodynamically stable, the triprotonated ion is only kinetically stable. The pyrolysis of A-acctylthiourea and A.A -diacetyIthiourea (335) are ultimolecular first-order eliminations.83 Acid-catalysed ethanolysis of N,N -di- and tri-substituted aryl- and alkylaryl-thioureas gives 0-ethyl AAaryl thiocarbamates and amines.303 The acid-catalysed hydrolysis of thiourea was first order in thiourea and acid.304... 

Mean clearance (CL) values for cetuximab are displayed as a function of dose in Fig. 14.3. Mean CL values decreased from 0.079 to 0.018 L/h/m2 after single cetuximab doses of 20 to 500 mg/m2, respectively. In the dose range 20 to 200 mg/m2, CL values decreased with dose. At doses of 200 mg/m2 and greater, CL values leveled off at a value of approximately 0.02 L/h/m2. This biphasic behavior suggests the existence of two elimination pathways. The elimination of cetuximab apparently involves a specific, capacity-limited elimination process that is saturable at therapeutic concentrations, in parallel with a nonspecific first-order elimination process that is non-saturable at therapeutic concentrations. Increasing doses of cetuximab will therefore ultimately lead to the saturation of the elimination process that is capacity-limited and that follows Michaelis-Menten kinetics, whereas the first-order process will become the dominant mechanism of elimination beyond a particular dose range. 

First-order dehydrohalogenation usually takes place in a good ionizing solvent (such as an alcohol or water), without a strong nucleophile or base to force second-order kinetics. The substrate is usually a secondary or tertiary alkyl halide. First-order elimination requires ionization to form a carbocation, which loses a proton to a weak base... 

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).

In the disposition model shown in Figure 4.9, the kinetics of drug distribution and elimination are represented by a single compartment with first-order elimination as described by the equation... 

When a drug is subject to first-order kinetics and by definition the rate of elimination is proportional to plasma concentration, then the t) is a constant characteristic, i.e. a constant value can be quoted throughout the plasma concentration range (accepting that there will be variation in t) between individuals), and this is convenient. If the rate of a process, e.g. removal from the plasma by metabolism, is not directly proportional to plasma concentration, then the t) cannot be constant. Consequently, when a drug exhibits zero-order elimination kinetics no single value for its t] can be quoted for, in fact, t) decreases as plasma concentration falls and the calculations on elimination and dosing that are so easy with first-order elimination (see below) become too complicated to be of much practical use. 

A study in rats using radiolabeled EGb 761 revealed a half-life of 4.5 hours, with elimination following first-order (linear) kinetics (19). 

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