Tissue elimination

The polymyxins are slowly excreted by glomerular filtration the slow elimination rate is due to binding in tissues. Elimination is decreased in patients with renal disease, and drug accumulation can lead to toxicity. Sodium coUstimethate, the parenteral preparation, binds less to tissue and is excreted faster than the free base. 

Long tissue elimination half-life cleared by nuclease-mediated metabolism. 

Fig. 7.1 Two-compartment open model with plasma and tissue elimination.

From an examination of Eq. (6) for a two-compartment model it is evident that Vss is dependent on the quantification of K12 and K21. For this model K12 and K21 can be determined by nonlinear regression analysis of plasma concentration-time data, either by deriving them from the fitted values of the coefficients and exponentials of the bi-exponential expression describing the concentration-time data, or by coding them directly into the modeling program. For the case where tissue elimination exists, it is possible to code into the model the existence of a K20, but the convergence process will not be able to resolve the appropriate micro rate constant. 

Note that in a two-compartment model with tissue elimination theis ... 

From these simulations based on a two-compartment model with both plasma and tissue elimination, a Vss determined by utilizing noncompartmentai methods will have a value less than the true Vss. These simulations also show that the shape of the plasma concentration-time curve and the relative magnitudes of the plasma and tissue elimination rate constants do not correlate with the error. However, this error does tend to be greater for hypothetical drugs that are more extensively eliminated by tissue routes. 

TABLE 9.2 Tissue Treatment Volume as a Function of Tissue Elimination Half-Life... 

Tissue treatment volumes of the substance being infused are a strong function of the tissue elimination half-life, which reflects the sum of both metabolic and micro vascular tissue clearances. Table 9.2 summarizes how this treatment volume and associated penetration distance varies with the characteristic tissue elimination half-life of the infused species. Various elimination half-lives were used for these simulations and an infusion rate of 3 pL/min into brain for 12 hours was assumed. For the extreme case of a macromolecule undergoing no metabolism, the treatment volume is 27 cm, with a penetration distance of 1.9 cm. For a more realistic tissue elimination half-life, as might be encountered with weakly binding monoclonal antibodies or stabilized analogs of somatostatin or enkephalin peptides, this volume and the distance, respectively, decrease only to 14 cm and 1.5 cm. 

FARAD estimates of withholding intervals may rely on pharmacokinetic data to help define the final terminal elimination phase of a drug. In these cases, it is assumed that the final edible tissue elimination phase will be at least as long as that observed in blood. Although specific safety factors are not built into these estimates, the estimated withholding times are expanded to help ensure that residues drop well below the established tolerance by the end of the recommended period. ... 

Methomyl is rapidly absorbed from the oral route. Dermal exposure is less hazardous. It is biotransformed to acetonitrile and carbon dioxide. Methomyl is well distributed to the tissues. Elimination is rapid less than 10% remains 24 h after an oral exposure. Approximately 75% of an absorbed oral... 

The plasma half-life is approximately 6 hours, because the drug is rapidly bound to bone tissue. Elimination half-life is approximately 3 days. Once bound to bone tissue, however, the drug half-life becomes greater than 10 years. 

The liver extensively metabolizes all three agents, and the conjugates and metabolites are excreted in the bile. Only a small fraction of a dose (<15%) is found in the urine unchanged. In patients with hepatic dysfunction (bilirubin >3 mg/dL), a 75% reduction in dose of any of the vinca alkaloids is advisable. The pharmacokinetics of each of the three drugs are similar, with central and tissue elimination half-lives of 1 and 20 hours for vincristine, 3 and 23 hours for vinblastine, and 1 and 45 hours for vinorelbine, respectively. 

S.A. Everett, M.A. Naylor, K.B. Patel, M.R.L. Stratford and P. Wardman, Bioreductively-activated prodmgs for targeting hypoxic tissues elimination of aspirin... 

Pharmacokinetics Metronidazole is effective orally and distributed widely to tissues. Elimination of the drug requires hepatic metabolism. 

Pharmacokinetics Etoposide is well absorbed after oral administration and distributes to most body tissues. Elimination of etoposide is mainly via the kidneys, and dose reductions should be made in patients with renal impairment. 

Bound residues of tetracyclines may occur in bones of slaughtered animals for months after treatment. Theoretically, these could reach the food chain via contaminated (mechanically deboned) meat or meat and bonemeal. The accumulation of tetracyclines in tissues is illustrated by the findings of Toutain and Raynaud for oxytetracycline in calves (Table 2.8). Concentrations of oxytetracycline were relatively high in liver and kidney compared to the extrapolated zero-time concentration for serum (4.2 mg/1). The time required for residues to deplete to 0.1 mg/1 in serum was 143 hr, considerably shorter than the time required for residues to deplete to 0.1 mg/kg in liver and kidney, but similar to the depletion time for muscle. The data nicely illustrate the importance of tissue elimination half-life in determining decrease to the 0.1 mg/kg concentration despite an almost three-fold higher initial concentration... 

Adding Hoagland s solution in addition to sunflower tissues eliminated the inhibitory effects of sunflower tissues on pigweed seedling biomass. Thus, it would appear that nutrients in plant tissues mixed into soil might modify plant-plant allelo-pathic interactions differently than nutrients/fertilizer directly applied to surface of the soil or mixed into the soil. The functional role of nutrients in small grain and clover cover crop residues is presently not known. 

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