Cumulative Excretion

Following oral administration of 1 mg/kg 14C mirex to a female rhesus monkey, 25% of the 14C was recovered in the feces within 48 hours, with a cumulative excretion of 26.5% over 23 days. Less than 1% was recovered in the urine over 23 days (Wiener et al. 1976). A monohydro derivative of mirex was identified in the feces of rhesus monkeys given daily doses of 1 mg/kg mirex (Stein and Pittman 1977). The exact duration of dosing was not specified (Stein and Pittman 1977). 

The cumulative excretion of P840 at 48 hours post-injection was found to be 65 21 % of the injected dose in the urine and 4 1 % in the faeces. Thus,... 

In the case of drugs renally eliminated in unchanged form, the half-life of elimination can be calculated from the cumulative excretion in urine the final total amount eliminated corresponds to the amount absorbed. 

The metabolism and kinetics of cyclohexanone were studied in a group of volunteers (four men and four women) during and after 8-h exposures to 101, 207 and 406 mg/m- . After exposure to 207 mg/m- , the metabolic yields of urinary cyclohexanol, 1,2- and 1,4-cyclohexanediol and their glucuronide conjugates were 1%, 39% and 18%, respectively. The elimination half-times (Aj of the 1,2- and 1,4-diols, respectively, were 16 h and 18 h. Consequently, after repeated exposure over five days, there was no cumulation of urinary cyclohexanol, whereas there was cumulative excretion of the diols. The permeation rate of cyclohexanone liquid through the skin was 37-69 nig/cm per hour, indicating that occupational exposure by this route is of minor importance (Mraz et al., 1994). 

In male Fischer 344 rats administered a single intratracheal dose of 0.32 g labeled 2,3,7,8-TCDD/kg, feces was the major route of excretion over a 3-day period after dosing (Diliberto et al. 1996). The cumulative excretion of 26.3% of the administered dose was observed over 3 days following exposure. Approximately 4% of the dose was excreted in the feces on day 3. The cumulative urinary excretion was only 1.3% of the administered dose. 

Figure 9. Cumulative excretion of label after administration of 3H-tx -THC in rat, rabbit, and human urine and feces (30)...

Fig. 3. Example for the time-course of a compound with a high first pass effect. The values for the perfusate represent the total amount of compound in the total volume of perfusate (100 ml nmol/ml x 100). The values for the bile represent the total excreted amount of compound in the bile per sampling period of 15 minutes ( xmol/ml x bile volume per 15 minutes) and were expressed as the values measured per sampling interval and as cumulative excreted into the bile.

For urine data, the individual and mean fractional and cumulative urinary excretion of XYZ1234 were calculated the cumulative excretion profiles were represented graphically fractional and total urinary excretion (Ae -tp Ae(0-48h))> urinary recovery (% of administered dose), and renal as well as non-renal clearance (CLR, CLNR) were determined. 

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. 

Cumulative excretion of radioactivity in the urine and faeces within 48 h of injection of the agents under study is shown in Fig. 5.6. The main... 

FIG. 5.6. Cumulative excretion of radioactivity in rats after injection of (a) DOTATATE, (b) In-DOTATATE, (c) I-DOTATATE and (d) Sm-DOTATATE (in percentage of injected dose). 

In a related study. Wester et al. (1990,1993) assessed the in vivo percutaneous absorption of PCBs in adult female Rhesus monkeys. " C-Labeled Aroclor 1242 and 1254 were separately administered iv and topically to Rhesus monkeys and urinary and fecal excretion of radioactivity was measured for the next 30 days. Following iv administration, the 30-day cumulative excretion was 55% of the administered dose (39% urine, 16% feces) for Aroclor 1242 and 27% (7% urine, 20% feces) for Aroclor 1254. The percentage of the dose absorbed following topical administration to abdominal skin (after light clipping of hair) was estimated from the ratio of the total urinary and fecal excretion following topical and iv administration. Topical administration of Aroclor 1242 in soil, mineral oil, tiichlorobenzene, or acetone resulted in 14, 20, 18, and 21% absorption of the administered dose, respectively. In contrast to the above in vitro results with human skin, the vehicle had little effect on the systemic absorption of the PCBs applied to the skin of monkeys. This may be due to the uncertain viability of the human skin used in the in vitro studies and the fact that the in vitro study primarily assessed retention of PCBs in human skin and could not estimate systemic absorption. 

FIGURE 14.13 Mean urinary ( ), fecal (O), and total ( ) cumulative excretion (168h) of 14C-ixabepilone derived from eight patients after intravenous administration of 70mg (80 nCi) 14C-ixabepilone over 3 h. Error bars represents the standard deviation. (Adapted from Beumer, J.H. et al., Invest. New Drugs, 25, 327, 2007. With permission.)... 

Metabolites of tea catechins are excreted in bile or urine. In general, small conjugates, such as monosulfates, tend to be excreted in urine, and extensively conjugated metabolites are more likely to be excreted in bile. The total amount of metabolites excreted in urine correlated roughly with maximum plasma concentrations. " The exact half-lives of tea catechins in plasma were calculated to be in the order of 2-3 h, except for EGCG, which is eliminated more slowly. " Relative urinary excretion data were used to estimate the minimal absorption rate and were consistent with the plasma kinetic data for most catechins, but for EGCG that mostly excreted in bile, the urinary excretion rate was very small (0-0.1%), and its absorption was underestimated. The urinary excretion rates of EC and EGC were 18.5 and 11.1%, respectively. The low cumulative excretion of tea catechins in human urine, which was 0-9.8%, suggested that they were extensively metabolized in the human body. 

FIG. 6. Expanded model of in vivo folate metabolism. Tbe pools are defined as follows 1, rapid turnover folate 6, slow turnover folate (tissues) 2, irretrievable losses by fecal excretion and catabolism 3, cumulative excretion of urinary folate 4, fractional (daily) excretion of urinary folate. Analysis was performed with parallel models for labeled and nonlabeled folate. 

A study in 6 healthy subjects found that the cumulative 72-hour urinary excretion of unchanged dextropropoxyphene was increased sixfold by acidification of the urine with oral ammonium chloride and reduced by 95% by alkalinisation with sodium bicarbonate the half-life of dextropropoxyphene was also shortened by ammonium chloride. The excretion of the active metabolite norpropoxyphene was much less dependent on urinary pH. However, the cumulative excretion of dextropropoxyphene and norpropoxyphene, even into acidic urine, accounted for less than 25% of the dose during 72 hours. ... 

A study in 10 patients with small cell bronchogenic carcinoma taking methotrexate found that when they were also given a range of oral anti-in-feetives (paromomycin, vancomycin, polymyxin B, nystatin) the urinary recovery of methotrexate was reduced by over one-third (from 69% to 44%). The paromomycin was believed to have been responsible. In another study the concurrent use of neomycin 500 mg four times a day for 3 days reduced the methotrexate AUC and the 72-hour cumulative excretion by 50%. In contrast, the same report suggests that kanamycin can increase the absorption of methotrexate, but no details are given. 

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. 

Figures 1 and 2. Cumulative excretion of 15 N as renal uric acid after a single oral dose of 15 N-glycine (67 mg/kg). 4 and 5 subject number.

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