Elimination rate

Alkyl mercury compounds in the blood stream are found mainly in the blood cehs, and only to a smah extent in the plasma. This is probably the result of the greater stabhity of the alkyl mercuric compounds, as well as their pecuflar solubiUty characteristics. Alkyl mercury compounds affect the central nervous system and accumulate in the brain (17,18). Elimination of alkyl mercury compounds from the body is somewhat slower than that of inorganic mercury compounds and the aryl and alkoxy mercurials. Methylmercury is eliminated from humans at a rate indicating a half-life of 50—60 d (19) inorganic mercurials leave the body according to a half-life pattern of 30—60 d (20). Elimination rates are dependent not only on the nature of the compound but also on the dosage, method of intake, and the rate of intake (21,22). 

In cases of all but intravenous adininistration, dosage forms must make the active moiety available for absorption, ie, for dmg release. This influences the bioavailabiUty and the dmg s pharmacokinetic profile. Ideally the dmg is made available to the blood for distribution and elimination at a rate equal to those processes. Through technological developments dmg product design can achieve release, absorption, and elimination rates resulting in durations of activity of 8—12 hours, ie, prolonged action/controlled release dmg products (21,22). Such products improve the compliance rate of dmg usage by patients. 

In addition to the elimination rate constant, the half-life (T/i) another important parameter that characterizes the time-course of chemical compounds in the body. The elimination half-life (t-1/2) is the time to reduce the concentration of a chemical in plasma to half of its original level. The relationship of half-life to the elimination rate constant is ti/2 = 0.693/ki,i and, therefore, the half-life of a chemical compound can be determined after the determination of k j from the slope of the line. The half-life can also be determined through visual inspection from the log C versus time plot (Fig. 5.40). For compounds that are eliminated through first-order kinetics, the time required for the plasma concentration to be decreased by one half is constant. It is impottant to understand that the half-life of chemicals that are eliminated by first-order kinetics is independent of dose. ... 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

According to the basic natural law, the time-dependent decrease (-cL4/d() is proportional to the actual amount of a drag (A) in the body. The proportionality constant is the elimination rate Ke). 

Pharmacokinetics. Figure 1 Main pharmacokinetic processes and parameters Half-life (T1/2), volume (Vd), elimination rate constant (Ke), and clearance (Cl). 

The volume will decrease when renal impairment is associated with a decrease in the elimination rate beta (betaNorm => betaFail). On the other side, the volume will increase when the free plasma fraction (fp) increases in renal impairment where jp = 1 - PB%. The volume decreases, when the free tissue fraction (ft) increases in renal impairment. 

In open-chain compounds, the molecule can usually adopt that conformation in which H and X are anti periplanar. However, in cyclic systems this is not always the case. There are nine stereoisomers of 1,2,3,4,5,6-hexachlorocy-clohexane seven meso forms and a dl pair (see p. 161). Four of the meso compounds and the dl pair (all that were then known) were subjected to elimination of HCl. Only one of these (1) has no Cl trans to an H. Of the other isomers, the fastest elimination rate was about three times as fast as the... 

In a study of pregnant rats that were exposed to radiolabeled methyl parathion by single dermal application, half-life elimination rate constants for various tissues ranged from 0.04 to 0.07 hour, highest values noted in plasma, kidneys, and fetus. Of the applied radioactivity, 14% was recovered in the urine in the first hour postapplication. By the end of the 96-hour study, 91% of the applied dose had been recovered in the urine. Fecal excretion accounted for only 3% of the administered dose (Abu-Qare et al. 2000). 

The area under the PCP concentration-time curve (AUC) from the time of antibody administration to the last measured concentration (Cn) was determined by the trapezoidal rule. The remaining area from Cn to time infinity was calculated by dividing Cn by the terminal elimination rate constant. By using dose, AUC, and the terminal elimination rate constant, we were able to calculate the terminal elimination half-life, systemic clearance, and the volume of distribution. Renal clearance was determined from the total amount of PCP appearing in the urine, divided by AUC. Unbound clearances were calculated based on unbound concentrations of PCP. The control values are from studies performed in our laboratory on dogs administered similar radioactive doses (i.e., 2.4 to 6.5 pg of PCP) (Woodworth et al., in press). Only one of the dogs (dog C) was used in both studies. 

The data used are given in Table I. The elimination rate constants included were determined at 20° C. (5). The toxicity to mosquito larvae, given as median lethal dosages (concentration in parts per million of water required to cause 50% mortality in 48 hours), was estimated from the data of Deonier et al. (9) and is probably reproducible to within 30%. 

A statistical test of these data gave a correlation coefficient of 0.968 (19), with only 0.834 required for 1% significance. Thus the elimination rates are functions dependent... 

Thus, the overall elimination rate constant (ke[) here is the sum of the urinary excretion rate constant (ke) and the metabolism rate constant (km) ... 

Db = drug in the body De = eliminated drug ka = first-order absorption rate constant kei = overall elimination rate constant... 

Thus after 6 hours the semilog plot of Cp versus time shown in Fig. 10 becomes a straight line and kei can be determined from the slope. Therefore, the overall elimination rate constant for a drug may be accurately determined from the tail of a semilog plot of plasma concentration versus time following extravascular administration if ka is at least five times larger than kei. 

Example. A tablet containing 100 mg of a drug was administered to a healthy volunteer and the plasma concentration (Cp) versus time data shown in Table 6 were obtained. Figure 11 shows a semi-log plot of these Cp versus time data. The half-life for elimination of the drug can be estimated from the straight line tail of the plot to be 4.7 hours. The overall elimination rate constant is then... 

The usual goal of an oral sustained-release product is to maintain therapeutic blood levels over an extended period. To achieve this, drug must enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by the half-life (t /2). Each drug has its own characteristic elimination rate, which is the sum of all elimination processes, including metabolism, urinary excretion, and all other processes that permanently remove drug from the bloodstream. 

Other applications of the previously described optimization techniques are beginning to appear regularly in the pharmaceutical literature. A literature search in Chemical Abstracts on process optimization in pharmaceuticals yielded 17 articles in the 1990-1993 time-frame. An additional 18 articles were found between 1985 and 1990 for the same narrow subject. This simple literature search indicates a resurgence in the use of optimization techniques in the pharmaceutical industry. In addition, these same techniques have been applied not only to the physical properties of a tablet formulation, but also to the biological properties and the in-vivo performance of the product [30,31]. In addition to the usual tablet properties the authors studied the following pharmacokinetic parameters (a) time of the peak plasma concentration, (b) lag time, (c) absorption rate constant, and (d) elimination rate constant. The graphs in Fig. 15 show that for the drug hydrochlorothiazide, the time of the plasma peak and the absorption rate constant could, indeed, be... 

Elimination rate constant in fish Aelimination fish day-1 N2(—4.79,1.42)... 

Figure 10.18 DOC-elimination rate curves for poly(vinyl alcohol) with optimally adapted and non-adapted inoculum according to the Zahn-Wellens test [212]... 

Both ADH and ALDH use NAD+ as cofactor in the oxidation of ethanol to acetaldehyde. The rate of alcohol metabolism is determined not only by the amount of ADH and ALDH2 enzyme in tissue and by their functional characteristics, but also by the concentrations of the cofactors NAD+ and NADH and of ethanol and acetaldehyde in the cellular compartments (i.e., cytosol and mitochondria). Environmental influences on elimination rate can occur through changes in the redox ratio of NAD+/NADH and through changes in hepatic blood flow. The equilib-... 

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