Excretion curves, cumulative

Techniques which utilize continuously perfused, "dynamic diffusion cells maintain "sink" conditions, and serial samples may be collected in automated fraction collectors. When these samples are added, the cumulative amount removed ("excreted") from the diffusion cell as a function of time is obtained. This Is not Identical to cumulative absorption, which is the sum of the amount excreted (EXC) plus the residual amount (RA) still remaining In the diffusion cell. Thus, the continuous perfusion technique is limited by the ability of the resulting cumulative excretion curve to approximate the true cumulative percutaneous absorption curve. Two methods of approximation may be employed. Both depend on an understanding of the kinetic parameters which define the diffusion cell system being utilized. 

The cumulative excretion curves depicted In Figure 2 are described by the equation... 

The profiles demonstrate that when Ke Is only slightly larger than Ka, a substantial lag occurs before peak flux (rate of rise of the cumulative excretion curve) Is obtained. As Ke Increases, the term exp(-Ke t) approaches 0 more quickly, and Equation 5 reduces to Equation 4. We may effect a reduction of Equation 5 to Equation 4 by assuming that this exponential approaches 0 when It Is 95% complete, l.e.. 

Relationship of cumulative excretion curves (broken lines) to the cumulative absorption curve (solid line). 

Once this value of t has been exceeded, the reduction to Equation 4 has been effected and the remainder of the cumulative excretion curve Is dependent on the absorption process only. Thus, as the value of Ke Increases, the excretion curve approximates the absorption curve more closely. 

If a reliable estimate of P Is to be obtained from a cumulative excretion curve generated by a continuously perfused, dynamic" diffusion cell, data points must be selected after the value of t defined by Equation 7 has been surpassed (when the shape of the excretion curve becomes dependent on absorption only), but before 10-15% of the total available dose has been absorbed (l.e., during the "steady state" period of absorption). Inspection of Figure 2 demonstrates that data points selected before or after these boundary conditions may lead to determinations of P which are falsely low. 

Wagner has claimed that evaluation of the time course of urinary excretion of metabolites on the assumption of rapid clearance may lead to an erroneous conclusion of saturation of metabolic pathways. He also stated that the apparent linearity of a cumulative urinary excretion curve and/or the curvature of semilogarithmic plots of drug blood levels or of amounts of drug-not-excreted against time are insufficient evidences to conclude zero order steps in metabolite production or zero order absoiTption... 

Sohn et al. [148] examined the kinetic variables of omeprazole and its two primary metabolites in plasma, 5-hydroxyomeprazole and omeprazole sulfone, and the excretion profile of its principal metabolite in urine, 5-hydroxyomeprazole, in eight extensive metabolizers and eight poor metabolizers. Each subject received a postoral dose of 20 mg of omeprazole as an enteric-coated formulation, and blood and urine samples were collected up to 24 h postdose. Omeprazole and its metabolites were measured by HPLC with UV detection. The mean omeprazole area under the concentration-time curve, elimination half-life, and apparent postoral clearance were significantly greater, longer, and lower, respectively, in the poor metabolizers than in the extensive metabolizers. The mean cumulative urinary excretion of 5-hydroxyomeprazole up to 24 h postdose was significantly less in the poor metabolizers than in the extensive metabolizers. 

When the labeled atropine was administered to both mice and rats by both Intravenous and Intraperltoneal Injections, the cumulative excretion of In the urine by the mouse was always considerably greater than that by the rat. The label from alpha-[ C]acroplne Injected intravenously Into mice appeared In their urine slightly more promptly and to a somewhat greater extent chan chat from labeled atropine that had been Injected Intraperltoneally or subcutaneously or Chat had been administered by gavage. The curve for the clearance of from the body of the mouse with time elapsed after subcutaneous Injection of the labeled alkaloid required three simultaneous exponential equations to represent the observations after a period of latency of about 45 min, during which excretion of followed none of the three exponential relationships. In addition to atropine itself, at least three other substances containing appeared In the urine of the mouse. 

Figure 5. Cumulative -radioactivity (10 dpm) excreted as CO2. Plotted curve calculated using the...

The excretion of C-radioactivity with urine is also represented by the empirical model (Figure 8). The calculated curve of the cumulative C-radioactivity in urine is shown in Figure 7 together with the experimental data. 

Fig. 3.2 Analogue computer-generated curves showing the levels (as fraction of the intravenous dose) of benzylpenicillin in the central (serum) and peripheral (tissue) compartments of the two-compartment pharmacokinetic model and the cumulative amount excreted unchanged in the urine as a function of time. The curves are based on the first-order rate constants (k12, k21, kel) associated with the compartmental pharmacokinetic model. Note...

An approximated cumulative absorption curve may thus be generated from excretion rate data by adding RA to AUC for each collected sample, and P subsequently determined in the usual fashion. 

Cumulative absorption curves were approximated using the AUC + RA method from excretion rate data as described above. The total dose available for absorption was considered to be the sum of all the amounts recovered from skin surface washings, tissue digestion, and cumulative absorption through skin (see below). 

Figure 16. Semilogarithmic plot of the time course of decline of radioactivity from the whole body, serum, and extravascular pools following intravenous administration of IgG. The radioactivity retained in the body (E + P ) was determined by cumulative subtraction of the radioactivity excreted in the urine from the injected activity. The curve of activity in the extravascular pool (E ) was determined by subtracting the activity in the plasma pool (P ) from that retained in the whole body (E + P ). Reproduced with permission from Waldmann and Strober (1%9) copyright 1%9, S. Karger, AG, Basel.

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