Oral dose, excretion differences

Because these experiments illustrate the excretion differences between dermal. Intramuscular, and oral dose excretion, the excretion differences between compounds, and also problems about which urinary metabolite to monitor (see 44). a very comprehensive experimental design would be necessary to correctly model dermal exposure, absorption, and urinary metabolite levels. Statistical problems, centering around replicate variation and the resulting necessity for abnormally large numbers of replications, could drive the costs of such an experiment In small animals, and certainly in humans, to prohibitively high levels. 

The dose of TCDD given to the male rats used in this study, 50 />tg/kg, was approximately twice the LD50, 23 /xg/kg. This large dose was necessary because of the low specific activity of the TCDD- C used. In this study rats lost weight, and their physical condition was poor, which typifies the insidious response to TCDD (J). Survival of the rats for 21 days was not totally unexpected because in previous studies on the lethality of TCDD deaths frequently occurred 20 or more days following a single oral dose of similar magnitude (I). With doses that do not induce untoward effects, the compound may be excreted at a different rate. 

Urine is the principal excretory route for elimination of diisopropyl methylphosphonate after oral administration to mice, rats, pigs, mink, or dogs (Hart 1976 Snodgrass and Metker 1992 Weiss et al. 1994). However, the rate of excretion differs among species. Peak urinary excretion of a single oral dose of 225 mg/kg [14C]-radiolabeled diisopropyl methylphosphonate occurred at 6 hours in mice,... 

Excretion kinetics of chlordane are complex, and different isomers exit through different pathways (USEPA 1980, 1988). In rats, chlordane elimination was almost complete 7 days after receiving single oral doses up to 1 mg/kg body weight (BW) 24 hours after treatment, 70% of the r/. v-chlordane and 60% of the trans-chlordane had been excreted (WHO 1984). In rodents, chlordane and its metabolites were usually excreted in feces, regardless of the administration route the cis-isomer was excreted slightly faster than the trans-isomer, although identical metabolites seemed to be formed (Menzie 1969, 1980 USEPA 1980 WHO 1984 Nomeir and Hajjar 1987). In rabbits, however, up to 47% of the administered dose was voided in the urine, and cis- and /ran.v-chlordanc were excreted at the same rate (Nomeir and Hajjar 1987). 

Oral doses of piperazine are readily absorbed with peak plasma levels 2 hours after dosing. The drug is excreted in the urine with an elimination half-life of about 3 hours. However large interindividual differences were found for the excretion rate of both unchanged drug and its metabolites. 

There are important quantitative differences between species in the routes of elimination of coumarin metabolites. In rats, biliary excretion occurs with an appreciable proportion of the dose excreted in the faeces (Cohen, 1979 Lake, 1999). For example, after a 50-mg/kg bw oral or intraperitoneal dose of coumarin to rats, some 50% was excreted in the bile as unknown metabolites within 24 h (Williams et al., 1965). The urine appears to be the major route of coumarin excretion in Syrian hamsters, rabbits and baboons, but not in marmosets (Kaighen Williams, 1961 Waller Chasseaud, 1981 Lake et al, 1989a, 1990 Lake, 1999). 

Fishman and coworkers,220 reported that, following an oral dose of 5 to 10 g. of D-glucuronolactone, about 16% was excreted in the urine as D-glu-curonic acid by normal, human subjects. An intravenous dose of 2 to 3 g. was followed by the excretion of 46-65%.219 221 The data of Fretwurst and Ahlhelm222 are similar. Quantitative differences in D-glucuronolactone metabolism in arthritic, hepatic, and mesenchymal tissue diseases were claimed to have been found by the above workers, but the differences were generally not remarkable. 

Studies in animals reveal differences among species and between animals and humans. Maximum blood DNOC concentrations of 72.2 pg/g at 6 hours after the last dose of 20 mg/kg/day for 9 days and 105 pg/g at 3.5 hours after a single dose of 30 mg/kg DNOC were found in rats (King and Harvey 1953b). When rabbits were similarly treated, peak values were 54.7 pg/g at 4.5 hours after multiple doses of 25 mg/kg/day DNOC and 49.5 pg/g at 6 hours after a single dose of 30 mg/kg. Blood DNOC levels of 25, 34, and 50 pg/g were detected in rabbits given single oral doses of 10, 15, or 18 mg/kg DNOC, respectively (Truhaut and De Lavaur 1967). Urinary excretion of DNOC and its metabolite, 6-amino-4-nitro-o-cresol, accounted for 25-38% of the 10-15 mg/kg/day doses in 3 days. Of this, 87-97% was excreted in the first day. 

Target Tissues. The model correctly described metabolic differences observed between mice and rats. For instance, mice metabolize benzene more efficiently than rats during and after a 6-hour inhalation exposure. After oral exposure, mice and rats metabolized doses of benzene up to 50 mg/kg in a similar manner. At oral doses above 50 mg/kg, rats metabolized more benzene than did mice on a per kg body weight basis. Similar results were seen with the excretion of individual metabolites. Excretion of major metabolites, the phenyl conjugates, was similar for both species for oral doses up to 20 mg/kg, after which rats produced more phenyl conjugates than did mice. After inhalation, mice produced more phenyl conjugates at all exposure levels compared to rats when normalized to body weight. For hydroquinone metabolites, however, mice produce far more after both oral and inhalation exposure than rats. For muconic acid, the model predictions indicate that after inhalation exposure, mice produced more than rats after oral exposure, the relative amount of muconic acid produced by the two species was similar. 

Auranofin is a triethylphosphine gold derivative for oral administration. It is in some respects strikingly different from the rest. Some 25% of an oral dose is absorbed through the intestinal wall and blood concentrations are some 15-25% of those reached with parenteral therapy. Auranofin is bound to cellular elements of the blood, is excreted mainly in the feces, and exhibits less tissue retention and total body gold accumulation than parenteral forms. It is more effective in acute inflammatory models and is a potent inhibitor of lysosomal enzyme release, antibody-dependent cellular toxicity, and superoxide production. Auranofin also affects humoral and cellular immune reactions. However, some have found auranofin to be rather less effective than parenteral gold. Auranofin is used in doses of 2-9 mg/day (generally 6 mg/day), which is less than the dose originally recommended. 

The drug is rapidly absorbed after oral administration, and peak plasma concentrations occnr abont 1 honr later. Buspirone is extensively metabolized, with less than 1% of an administered dose excreted nnchanged. Important rontes of biotransformation are hydroxylation and oxidative dealkylation, the latter yielding l-(2-pyrimidinyl) piperazines. This metabolite has been shown to concentrate in the brain and to have pharmacologic activity, thongh its capacity to interact with different brain receptors appears to differ from that of buspirone. 

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