Elimination phase

The toxic effect depends both on lipid and blood solubility. I his will be illustrated with an example of anesthetic gases. The solubility of dinitrous oxide (N2O) in blood is very small therefore, it very quickly saturates in the blood, and its effect on the central nervous system is quick, but because N,0 is not highly lipid soluble, it does not cause deep anesthesia. Halothane and diethyl ether, in contrast, are very lipid soluble, and their solubility in the blood is also high. Thus, their saturation in the blood takes place slowly. For the same reason, the increase of tissue concentration is a slow process. On the other hand, the depression of the central nervous system may become deep, and may even cause death. During the elimination phase, the same processes occur in reverse order. N2O is rapidly eliminated whereas the elimination of halothane and diethyl ether is slow. In addition, only a small part of halothane and diethyl ether are eliminated via the lungs. They require first biotransformation and then elimination of the metabolites through the kidneys into the... 

NOTE The dotted lines at-e used to connect sequential time points. The solid line is a ilnear regression fit of the log-linear terminal elimination phase. 

Plasma concentrations should be obtained at steady state, usually after a minimum of 1 week at constant dosage. Sampling should be done during the elimination phase, usually in the morning, 12 hours after the last dose. Samples collected in this manner are comparable for patients on once-daily, twice-daily, or thrice-daily regimens. 

After Cmax and distribution equilibrium have been reached, the subsequent drug elimination phase can generally be described by first-order kinetics. The time-dependent decrease in drug-plasma concentration is paralleled by a corresponding decrease in elimination rate. Under these conditions, the plasma concentration of the drug at time t is given by Eq. (3.1). 

Computation of oral absorption (kj and elimination (E) rates is often complicated by the flip-flop of the absorption and elimination phases when they differ by less than a factor of 3. Because of these analysis problems, computation of absorption and elimination rates should not be attempted on the basis of oral dosing results alone. 

Tissue blood partition coefficients (R ) should be determined when steady-state has been achieved. Estimates based on samples obtained during the elimination phase following a single dose of the test substance may lead to underestimates of this ratio in both eliminating and noneliminating tissues unless its half-life is very long. Correction of these values for elimination has been described by several authors (Yacobi et al., 1989 Shargel and Yu, 1999 Renwick, 2000). 

The equation is compiled in the same way as that for a two-compartment model B.e-/3f continues to represent the terminal elimination phase and the term C.e 7f is added to represent slowly equilibrating compartments. 

The distribution and excretion of tritiated vincristine were studied by Castle and colleagues in rats and dogs (36). These investigators found that the drug was eliminated from the blood of both species in a biexponential manner, with half-lives of approximately 15 and 75 min. The persistence of low levels of radioactivity in the blood at late sampling times suggested that a third, very slow elimination phase contributes to the pharmacoki-... 

The disappearance of tritiated vindesine from the blood of rats has been reported to be biphasic, with half-life estimates of 15 min (distribution) and 10 hr (elimination) (59) it is likely that the prolonged elimination phase represents a hybrid between the second elimination phase described above for vincristine and the prolonged third phase evident on inspection of log concentration-time plots for vincristine in the rat. Biliary excretion contributes heavily to the elimination of vindesine in the rat. The bioavailability of vindesine in the rat appears to be very poor. The distribution of vincristine to different tissues in the mouse has been correlated with the estimated concentration of tubulin in the tissues (40). Tubulin concentration was measured by the capacity of a tissue to bind colchicine (40) comparable relationships between tissue concentrations of vincristine and colchicine binding capacity were observed for the dog and the monkey, but it should be emphasized that the correlations were based on the assumption that tissue tubulin content is closely similar in the mouse, dog, and monkey. 

Half-lives estimated after the administration of vinblastine to patients were 4 min, 1.6 hr, and 25 hr, indicating rapid distribution of the drug to most tissues, relatively rapid clearance, and a subsequent slow terminal elimination process. The distribution and initial clearance phase for vincristine are kinetically comparable to those observed for vinblastine half-lives for these phases have been reported to be 4 min and 2.3 hr in studies with vincristine. The terminal elimination phase for vincristine has been reported to be three to four times longer than that estimated for vinblastine, and the slow elimination of vincristine from susceptible neuronal tissue has been suggested to play a role in the neurotoxicity commonly observed in clinical settings with vincristine but not with vinblastine 51). 

Smoking of a single cigarette yields peak plasma levels in the range of 25-50 ng/mL. The effects described on p. 110 become evident When intake stops, nicotine concentration in plasma shows an initial rapid fall, reflecting distribution into tissues, and a terminal elimination phase with a half-life of 2 h. Nicotine is degraded by oxidation. 

If after single dose administration, the blood samples are not collected at time intervals, which allow for a description of the whole plasma concentration time course, including the absorption, distribution, and elimination phase, the information obtained is limited. In particular, data should be available in the hrst hours after administration to cover the absorption phase. If measurements of the parent compound and its metabolite(s) are made in this period, this will allow assessment of an extensive first pass effect, i.e., when a substance after oral administration is transported via the portal vein to the liver where metabolism takes place before the substance enters the systemic circulation. 

Excretion - Following discontinuation of chronic oral therapy, amiodarone has a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 107 days. A much slower terminal plasma elimination phase shows a half-life of the parent compound of approximately 53 days. For the metabolite, mean plasma elimination half-life was approximately 61 days. Antiarrhythmic effects persist for weeks or months after the drug is discontinued. 

Renal function impairment Severe renal impairment significantly altered the disposition of trospium. A 4.5-fold and 2-fold increase in mean AUCo- and Cmax. respectively, and the appearance of an additional elimination phase with a long half-life (approximately 33 hours) was detected in... 

Metabolism/Excretion — Amphotericin B has a relatively short initial serum half-life of 24 hours, followed by a second elimination phase with a half-life of approximately 15 days. The drug is slowly excreted by the kidneys with 2% to 5% as the biologically active form. 

Value reported for few-acid Highly variable Elimination phase Apparent eUmination phase Temiinal phase, NR = not reported. 

The elimination rate of Li+ from the body is variable. It is quite rapid during the first 10 hours after ingestion, and this period accounts for about 40% of the total Li+ excretion. However, the remaining portion of the Li+ dose is excreted very slowly over 14 days. Because of this biphasic elimination rate, clinically useful serum Li+ concentrations are usually determined 12 hours after the last dose. This period assures a relatively accurate reflection of the Li+ concentration, since it is beyond the most variable portion (rapid elimination phase) of the Li+ elimination profile. 

The plasma half-life of dacarbazine is biphasic, with a distribution phase of 19 minutes and an elimination phase of 5 hours. The drug is not appreciably protein bound, and it does not enter the central nervous system... 

Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. The major routes of drug excretion are glomerular filtration andl active renal tubular secretion. 

The elimination half life (tVi) from elimination phase is... 

---