Elimination first-order

Once the steady-state concentration is known, the rate of dmg clearance determines how frequendy the dmg must be adininistered. Because most dmg elimination systems do not achieve saturation under therapeutic dosing regimens, clearance is independent of plasma concentration of the dmg. This first-order elimination of many dmgs means that a constant fraction of dmg is eliminated per unit time. In the simplest case, clearance can be deterrnined by the dose and the area under the curve (AUC) describing dmg concentration as a function of total time ... 

The concentration of a- and P-endosulfan in the urine of a pest control worker who wore protective equipment peaked at 0.2 days (approximately 5 hours) after completing a 25-minute application of endosulfan in a greenhouse, declined to control levels by about 1.5 days postexposure, and remained at levels comparable to controls until the end of sampling at 3-days postexposure (Arrebola et al. 1999). Assuming first-order elimination, the urinary elimination half-Ufe was estimated to be 0.94 days for a-endosulfan and 1.16 days for p-endosulfan no endosulfan metabolite was detected in any urine sample. 

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). 

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... 

In Eq. (3.4), doseiv is the amount of drug administered intravenously, AUC is total area under the drug concentration-time curve, and k is the first-order elimination rate constant... 

This time a constant amount of drug is eliminated in a given time rather than a constant proportion. First-order elimination may become zero order when the elimination system (often a metabolic pathway) is saturated. 

The time evolution of plasma drug concentration can be treated by a simple model that assumes first-order absorption and first-order elimination of the drug. If [Dq] is the effective concentration of the drug dose, appearance of drug in the plasma will obey the relationship ... 

As shown above, the plasma drug concentration usually exhibits a biphasic rise and fall that are characteristic of all two-step series first-order processes. When k is zero, there will only be first-order absorption without any elimination, and when k > k, drug absorption will be virtually instantaneous, followed by first-order elimination. 

This is usually referred to as first-order elimination. When clearance is first-order, it can be estimated by calculating the area under the curve (AUC) of the time-concentration profile after a dose. Clearance is calculated from the dose divided by the AUC. 

When a compound is administered by a route other than intravenously, the plasma level profile will be different, as there will be an absorption phase, and so the profile will be a composite picture of absorption in addition to distribution and elimination (Fig. 3.26). Just as first-order elimination is defined by a rate constant, so also is absorption kab. This can be determined from the profile by the method of residuals. Thus, the straight portion of the semilog plot of plasma level against time is extrapolated to the y axis. Then each of the actual plasma level points, which deviate from this during the absorptive phase, are subtracted from the equivalent time point on the extrapolated line. The differences are then plotted, and a straight line should result. The slope of this line can be used to calculate the absorption rate constant kab (Fig. 3.26). The volume of distribution should not really be determined from the plasma level after oral administration (or other routes except intravenous) as the administered dose may not be the same as the absorbed dose. This may be because of first-pass metabolism (see above), or incomplete absorption, and will be apparent from a comparison of the plasma... 

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

A two-compartment open linear model has been described for the pharmacokinetic profile of cocaine after intravenous administration.14 The distribution phase after cocaine administration is rapid and the elimination half-life estimated as 31 to 82 min.14 Cone9 fitted data to a two-compartment model with bolus input and first-order elimination for the intravenous and smoked routes. For the intranasal route, data were fitted to a two-compartment model with first-order absorption and first-order elimination. The average elimination half-life (tx 2 3) was 244 min after intravenous administration, 272 min after smoked administration, and 299 min after intranasal administration. 

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... 

Reactivities and activation parameters for pyrolytic unimolecular first-order elimination reactions of A -acetylurea, A -acetylthiourca, /V,7V -diacetylthiourea and N-acetylthiobenzamide have been interpreted with reference to those for other amide derivatives.55 The first-order rate constants for pyrolysis of RCONHCSNHCe R (R = Me, R = H R = Ph, R = H, 4-N02, 3-C1, 4-C1, 4-Me) have also been measured at 423-500 K and correlated with Hammett [Pg.378]

First-order elimination rate constant K and half-life f1/2... 

The first-order elimination rate constant K can be determined as shown in Eq. (1.4) and has units of 1/time. The larger the value of K, the more rapidly elimination occurs. Once K has been determined, then calculating the half-life t1/2 is straightforward (Eq. 1.5). 

When plotted as In Cp versus time, a drug that undergoes first-order elimination generates a straight line (Figure 7.3). The slope is —keh and the y-intercept is In Cp°. Unlike Cp, In Cp can be less than 0, and the line for In Cp versus time can cross the x-axis. 

This equation assumes a one-compartment model and constant, first-order elimination. Based on Equation 7.17, the e kt term approaches 0 as t increases, and Cp approaches Rmi/kx]Vd. The value of 7 inf/A eiVd corresponds to Cpss (Equation 7.18). 

Valid values of F fall between 0 and 1. The term FD0/ Vd is related to the concentration of drug (same units as Cp) theoretically available to the bloodstream in the absence of elimination. Equation 7.21 assumes first-order elimination and a single compartment... 

Regardless of where a metabolite forms, Cp-time plots for metabolites often closely resemble Figure 7.20. The metabolite s Cp (Cpm) starts at 0 and rises to a peak. First-order elimination then becomes the predominant process, and Cpm begins to fall. Overall, the shape of the Cpm-time curve somewhat resembles Cp-time curve of an oral drug. 

Wagner [1] has shown, with IV bolus dosing, that the Vss for a n-compartment open mammillary model with first-order elimination from the central compartment is ... 

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