Subject half-life

Pharmacokinetics Clearance is higher in cancer patients compared to healthy subjects. Half-life 4 5 hr... 

For trace quantities of less than 100 ppm, the most successful method — and the most costly— is neutron activation. The sample is subjected to neutron bombardment in an accelerator where oxygen 16 is converted to unstable nitrogen 16 having a half-life of seven seconds. This is accompanied by emission of (J and 7 rays which are detected and measured. Oxygen concentrations as low as 10 ppm can be detected. At such levels, the problem is to find an acceptable blank sample. 

First, let us consider batch mixing processes, as exemplified by ordinaiy laboratory practice in solution kinetics. A portion of one solution (say, of the substrate) is added by pipet to a second solution (containing the reagent) in a flask, the flask is shaken to achieve homogeneity, and then samples are withdrawn at known times for analysis, or the solution is subjected to continuous observation as a function of time, for example, by spectrophotometry. For reactions on a time scale (measured by the half-life) of hours or even several minutes, the time consumed in these operations is a negligible portion of the reaction time, but as the half-life of the reaction decreases, it becomes necessary to consider these preliminary steps. Let us distinguish three stages ... 

A unique situation is encountered if Fe-M6ssbauer spectroscopy is applied for the study of spin-state transitions in iron complexes. The half-life of the excited state of the Fe nucleus involved in the Mossbauer experiment is tj/2 = 0.977 X 10 s which is related to the decay constant k by tj/2 = ln2/fe. The lifetime t = l//c is therefore = 1.410 x 10 s which value is just at the centre of the range estimated for the spin-state lifetime Tl = I/Zclh- Thus both the situations discussed above are expected to appear under suitable conditions in the Mossbauer spectra. The quantity of importance is here the nuclear Larmor precession frequency co . If the spin-state lifetime Tl = 1/feLH is long relative to the nuclear precession time l/co , i.e. Tl > l/o) , individual and sharp resonance lines for the two spin states are observed. On the other hand, if the spin-state lifetime is short and thus < l/o) , averaged spectra with intermediate values of quadrupole splitting A q and isomer shift 5 are found. For the intermediate case where Tl 1/cl , broadened and asymmetric resonance lines are obtained. These may be the subject of a lineshape analysis that will eventually produce values of rate constants for the dynamic spin-state inter-conversion process. The rate constants extracted from the spectra will be necessarily of the order of 10 -10 s"F... 

The discovery of two new elements started a frenetic race to find more. Actinium was soon unearthed (Debierne 1900) and many other substances were isolated from U and Th which also seemed to be new elements. One of these was discovered somewhat fortuitously. Several workers had noticed that the radioactivity of Th salts seemed to vary randomly with time and they noticed that the variation correlated with drafts in the lab, appearing to reflect a radioactive emanation which could be blown away from the surface of the Th. This Th-emanation was not attracted by charge and appeared to be a gas, °Rn, as it turns out, although Rutherford at first speculated that it was Th vapor. Rutherford swept some of the Th-emanation into a jar and repeatedly measured its ability to ionize air in order to assess its radioactivity. He was therefore the first to report an exponential decrease in radioactivity with time, and his 1900 paper on the subject introduced the familiar equation dN/dt = - iN, as well as the concept of half-lives (Rutherford 1900a). His measured half-life for the Th emanation of 60 seconds was remarkably close to our present assessment of 55.6 seconds for °Rn. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

In the foregoing example, the drug was administered to a healthy subject who had normal kidney and liver function. The estimated biological half-life in this... 

There are occasions when it is not possible to use a cross-over design in a bioequivalency determination. For example, if the half-life of the drug is very long, the required washout period between the two treatment periods may be several months. Obviously, it is quite impracticable to consider such a long washout period. Test subjects are unlikely to wait patiently for long periods of time, and thus if we tried to conduct a bioequivalency study with, say, a 3-month washout period, we would probably find that a significant number of our test subjects would not be available for the second dose. 

Some physiological variables influence the measurement of fibrinolytic activators and inhibitors. For instance, both t-PA and plasminogen activator inhibitor 1 (PAI-1) levels in plasma are subject to diurnal variation in a 12-hour period. Even in samples taken at the same time of day the coefficient of variation (CV) of measured PAI levels range from 8 to 143% To account for this diurnal variation, blood samples spaced over several time intervals during a 24-hour period should be collected. Consumption of alcohol induces the PAI level in plasma. The half-life of t-PA is 360 seconds. However, in the presence of trauma or inflammation, when the PAI-1 level is expected to be elevated 10-fold, the half-life of t-PA is reduced to 36 seconds (114). 

FIGURE 10 The half-life. It is impossible to predict when a radioisotope or an unstable substance (molecule) will decay or be decomposed. On an average, however, only half of any type of radioisotope or unstable substance (molecule) remains after one half-life (A/2) one-quarter will remain after two half-lives (A/A), one-eighth after three half-lives (A/8), and so on. The half-life is characteristic of every radioisotope and unstable molecule that of radioisotopes is not affected in any way by the physical or chemical conditions to which the radioisotope may be subjected. Not so the half-life of chemically unstable molecules, which is altered by changes in temperature and by other physical and chemical conditions. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

The main rout of excretion of the drug and its metabolites is the kidney with a half-life of 9-18 h in human. In contrast to human, animal models have a lower elimination half-life ranging from 0.6-9 h [78]. The elimination half-life of valproic acid and some metabolites was found to be much longer in the neonates (40-50 h) than adult subjects (9-18 h) [78,81]. One study reported no difference between the elimination half-life between elderly and young subjects (15.4 and 13.0 h, respectively) while other found an increase in for older patients (14.9 versus 7.2 h for young patients) [78,90], Insignificant amounts of valproic acid are found in breast milk, approximately 3% of maternal drug levels [84]. 

Radiotherapy generally involves cell destruction, requiring some form of particle emission on decay and a half-life between 1 and 10 days. The choice of a particular therapeutic application determines the type of particle emission (a, ft, or Auger e ), and the energy and half-life of the radionuclide to be used. Considerations include time for delivery of the radiopharmaceutical to its in vivo target, location of the target (tumor surface, tumor cell cytoplasm, tumor cell nucleus) and size of the tumor. The reader is directed to a number of reviews on this subject.15-22... 

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