Elimination half life determination

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

Short-term exposure to PCB mixtures that are rapidly eliminated may not result in the achievement of a steady-state blood level, in which case, the elimination half-life determined will be misleading. If a true half-life is substantially longer than the calculated half-life, the steady-state burdens may actually be higher than reported. On the other hand, an underestimate of half-life, given adequate steady-state body burden data, will result in an over-estimation of intake. 

However, for many AMDs and indeed drugs of other classes (e.g., anthelmintics), there has long been a practice of developing slow-release (depot) formulations, administered intramuscularly, subcutaneously, or as pour-on products, for use in farm animal species. As discussed in Section 2.2.3, these products commonly display flip-flop pharmacokinetics, in which the terminal half-life represents a slow absorption phase and is longer than the elimination half-life determined after intravenous dosing. The advantages and disadvantages of depot preparations are summarized in Table 2.15. 

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 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. 

Yoshimura et al. [132] studied the pharmacokinetics of primaquine in calves of 180—300 kg live weight. The drug was injected at 0.29 mg/kg (0.51 mg/kg as primaquine diphosphate) intravenously or subcutaneously and the plasma concentrations of primaquine and its metabolite carboxyprimaquine were determined by high performance liquid chromatography. The extrapolated concentration of primaquine at zero time after the intravenous administration was 0.5 0.48 pg/mL which decreased with an elimination half-life of 0.16 0.07 h. Primaquine was rapidly converted to carboxyprimaquine after either route of administration. The peak concentration of carboxyprimaquine was 0.5 0.08 pg/mL at 1.67 0.15 h after intravenous administration. The corresponding value was 0.47 0.07 pg/mL at 5.05 1.2 h after subcutaneous administration. The elimination half-lives of carboxyprimaquine after intravenous and subcutaneous administration were 15.06 0.99 h and 12.26 3.6 h, respectively. 

Individual metabolism cages are recommended for collecting urine and feces in oral dosing studies. Excreta should be collected for at least 5 elimination half-lives of the test substance. When urine concentrations will be used to determine elimination rates, sampling times should be less than one elimination half-life (taken directly from the bladder in IV studies) otherwise, samples should be taken at equal time intervals. 

When hydroxylation is absent or negligible, both the position of the acetylation-deacetylation equilibrium and the renal excretion rate determine the elimination half-life. This can be exemplified by comparing the SDM disposition in pigs and man. The renal clearance values of N -SDM in both species are the same ( approximately 10 ml/min/kg), but in man the equilibrium favours the acetylated... 

The plasma elimination half-life can be determined from a semi-logarithmic plot of the plasma concentration-time plot (Figure 5.2b), following an intravenous dose, as the time taken for the plasma concentration to fall by 50%. The elimination half-life of some drugs is very short (seconds or minutes) whereas for others it may be very long (weeks). 

The half-life determines the time it will take to achieve steady state and is useful for determining a dosing regimen. However, it does not give any clue to the processes involved in handling the drug, so that knowledge of the half-hfe alone cannot be used to make predictions about factors which are likely to affect the rate of elimination. 

Metabolism/Excretion - There are 2 genetically determined patterns of propafenone metabolism. In more than 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life of 2 to 10 hours. These patients metabolize propafenone into two active metabolites 5-hydroxypropafenone and N-depropylpropafenone. They both are usually present in concentrations less than 20% of propafenone. The saturable hydroxylation pathway is responsible for the nonlinear pharmacokinetic disposition. 

Although elimination half-life is usually associated with clearance, it should be noted that this parameter is also influenced by distribution. This concept is important to appreciate when individualizing drug therapy, since it is clearance that determines steady-state concentrations for any given dose absorbed. 

Because BZs are redistributed until over 95% of the drug is outside the blood circulation and the brain, it is the distribution half-life that is most important in determining the duration of action of each BZ. Unfortunately, it is the elimination half-life that is most studied and best known (see Table 27.1 Chouinard et ah, 1999). 

After an intramuscular dose of Avonex, serum levels of interferon beta-la peak between 3 and 15 hours and then decline at a rate consistent with a 10-hour elimination half-life. The terminal half-life of interferon beta-la after intravenous administration has been estimated at between 3 and 4 hours. Serum levels of interferon beta-la may be sustained after intramuscular administration due to prolonged absorption from the injection site. Systemic exposure, as determined by area under... 

In six male volunteers given 46 mg deuterium-labelled di(2-ethylhexyl) adipate [approx. 0.5 mg/kg bw] in com oil, 2-ethylhexanoic acid was the only metabolite that could be determined in the plasma. It had an elimination half-life of 1.65 h. In urine, the following metabolites were identified (percentage fraction of administered deuterium label) 2-ethylhexanoic acid (8.6%), 2-ethyl-5-hydroxyhexanoic acid (2.6%), 2-ethyl-1,6-hexanedioic acid (0.7%), 2-ethyl-5-ketohexanoic acid (0.2%) and 2-ethylhexanol (0.1%). The half-life for elimination of all metabolites excreted in the urine averaged 1.5 h, and none of the metabolites could be detected after 36 h (Loftus et al, 1993). 

Pharmacokinetics, safety, and antiviral effects of hypericin were studied in patients with chronic hepatitis C infection (Fig. 4) (71). The patients received an eight-weeks course of 0.05 and 0.10 mg/kg hypericin orally once a day. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 hours, respectively, for the doses of 0.05 and 0.10 mg/ kg) and mean AUC determinations of 1.5 and 3.1 pg/mL/hr, respectively. Because relatively high doses of 0.05 and O.lOmg/kg/day were given, which will probably be not reached after oral intake of recommended doses of SJW extract preparations, it is not surprising that hypericin caused a considerable phototoxicity in this study. 

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26-2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute). Local anesthetics are usually administered by injection into dermis and soft tissues around nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of local analgesia and the likelihood of CNS and cardiac toxicity. Topical application of local anesthetics (eg, transmucosal or transdermal) requires drug diffusion for both onset and offset of anesthetic effect. However, intracavitary (eg, intra-articular, intraperitoneal) administration is associated with a more rapid onset and shorter duration of local anesthetic effect. 

Sulfadiazine is a relatively short-acting sulfonamide with an elimination half-life of about 3 h in cattle. The importance of this drug for control of furunculoses in fish is determined by its combined use with the potentiator trimethoprim. 

Plasma peak concentrations are achieved within 2 h and the elimination half-life is about 12 h. Within the clinical dose range, there is high plasma protein binding ( 97%). Celecoxib is metabolized primarily via cytochrome P450 2C9 to three inactive main metabolites. It is excreted in faeces ( 57%) and urine ( 27%) as determined by administration of a single oral dose of radiolabeled drug. Celecoxib is given orally (200-400 mg/day). 

Clearance of cyclosporin A and its metabolites proceeds mainly through excretion of bile into faeces. After an oral dose of [3H]cyclosporin A, only 4-6% of the radioactivity is excreted in urine within 96 h. Intact [3H]cy-closporin A contributes only a small proportion of the excreted radioactivity (0.1-0.2% of the dose). The elimination half-life of cyclosporin A from blood, determined by HPLC, amounts to 15.8 8.4 h. 

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