Urinary excretion species differences

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,... 

No studies were located regarding toxicokinetic data in humans. Limited information is available regarding the toxicokinetic differences among animal species. Rats, mice, mink, and dogs showed rapid absorption, wide distribution, and over 90% urinary excretion of diisopropyl methylphosphonate or its metabolites. However, the rates of absorption and patterns of distribution varied (Hart 1976 Weiss et al. 1994). The mechanism of toxicity is also undetermined. From the limited data available, it is not possible to determine the degree of correlation between humans and animals. 

Tomokuni K, Ichiba M, Hirai Y. 1988. Species difference of urinary excretion of delta-aminolevulinic acid and coproporphyrin in mice and rats exposed in lead. Toxicol Lett 41 255-259. 

Urinary excretion patterns of thiocyanate suggest that there are quantitative species differences in acrylonitrile metabolism (Ahmed and Patel 1981). Thiocyanate was identified as a metabolite in rats, mice, rabbits and Chinese hamsters. About 20 to 23% of the administered dose was excreted as thiocyanate in rats, rabbits and Chinese hamsters, while 35% was excreted as thiocyanate in mice (Gut et al. 1975). It has also been observed that mice metabolize acrylonitrile more rapidly than rats (Ahmed and Patel 1981 Gut et al. 1975). Maximum blood cyanide concentrations were observed 1 hour after dosing in mice, but 3 hours after dosing in rats (Ahmed and Patel 1981). In mice, thiocyanate was present in the urine within 4 hours of dosing, while in rats, thiocyanate was present in urine only at time intervals longer than 4 hours (Gut et al. 1975). 

Piperazine and its salts are readily absorbed from the gastrointestinal tract, but nitrosation may occur in the stomach (32). The major portion of the absorbed drug is metabolized in tissues and the remainder, which is about 30-40%, is excreted in the urine. Piperazine is detectable in the urine as early as 0.5 h after drug administration. Although there is a wide variation in the rates at which piperazine is excreted by different animal species, urinary excretion is practically complete within 24 h. 

Benzyl acetate is quite soluble in lipids and therefore readily absorbed from the gastrointestinal tract and lung, as well as through the skin, in the species investigated. The absorption after oral administration in the rat was delayed if it was administered in com oil or propylene glycol as compared to neat [wet/zy/ene- Cjbenzyl acetate (Chidgey Caldwell, 1986) the peak plasma concentration of benzyl acetate-derived radioactivity occurred later after 1 h versus 4-6 h) and was lower at a 500 mg/kg benzyl acetate dose at 5 mg/kg benzyl acetate, there was no difference. The urinary excretion of the metabolites was also delayed by com oil, but the extent of absorption seemed not to be affected more than 80% was absorbed and excreted within 24 h, mainly in urine and, ultimately, less than 5% in faeces. In plasma and urine, no intact benzyl acetate was detected at any time only its metabolites were present (Chidgey Caldwell, 1986). Benzyl acetate is rapidly hydrolysed by esterases to benzyl alcohol and acetate (Yuan et al., 1995). These esterases are present in plasma and probably also in the tissues it is... 

Gipple KJ, Chan KT, Elvin AT, et al. Species differences in the urinary excretion of the novel primary amine conjugate tocainide carbamoyl O-beta-D-glucuronide. J Pharm Sci 1982 71 1011-1014. 

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. 

The question arises as to whether species differences also exist for passive renal excretion processes. Indeed, some more or less systematic and therefore controllable differences do exist. The urinary pH tends to be more acidic in carnivores than in herbivores. Due to differences in the degree of ionization, passive renal reabsorption of weak bases and acids thus will differ for the species mentioned, but in a reasonably predictable way. Also the degree of binding of the pharmacon to plasma albumin will influence the rate of renal excretion. 

Studies by Klotz et al. (1975,1976a,b) suggest that biliary excretion of diazepam is unimportant in man, but there is some evidence (see above) for species differences (Klotz etal., 1975,1976a van der Kleijn et al., 1971). Urinary excretion of diazepam is mainly in the form of sulphate and glu-curonide conjugates (Mandelli et al., 1978). The main metabolic pathway is demethylation and hydroxylation to metabolites with CNS depressant activity in animals and man. These metabolites are desmethyldiazepam and oxazepam. 

In all animal species studied thus far, the cinchona alkaloids are cleared rapidly from the blood and tissues once treatment is terminated. Most of this clearance results from degradation a smaller part is the consequence of urinary excretion. Both degradation and excretion vary wdth the differ-... 

Generally, 9a-F, 9a-CI, and 9a-Br substitution causes increased retention of urinary sodium with an order of activity in which F > Cl > Br, but species differences do exist. For these reasons, such compounds are not used internally in the treatment of diseases such as rheumatoid arthritis. Insertion of a 16a-0H group into the molecule affects the sodium retention activity so markedly that it not only negates the effect of the 9a-F atom but also causes sodium excretion. 

Metabolic profiles of urine and fecal samples generated in ADME studies provide information about the extent of metabolism and routes of excretion for parent and metabolites. The excretion of radioactivity after administration of gemopatrilat to healthy human volunteers shows that the compound is excreted in both urine and feces with most of the radioactive dose excreted by 48 h postdose. Based on urinary excretion, at least 55% of the dose is absorbed when administered orally. Figure 9.4 shows the comparative urinary and fecal profiles of orally administered gemopatrilat in rat, dog, and human (Wait et ah, 2006). These types of data representations help understand the quantitative and qualitative differences in metabolism across species. As can be clearly seen in Fig. 9.4, the drug is extensively metabolized in all species. 

Isoflurane is more resistant to biotransformation in man than are other volatile halogenated anaesthetics [201,241,245] although there can be metabolic variations in different animal species [245], An average recovery of95 percent has been obtained in exhaled air, while post-operative urinary excretion of ionic and bound organic fluoride accounted for less than 0.2 per cent of the total fluorine dose [201]. In a separate study of 9 surgical patients, serum inorganic fluoride levels were 4.4 0.4 umol dm 6 h after anaesthesia [241 ]. 

There are several studies on the effect of allopurinol and its metabolic derivatives on orotate phosphoribosyltransferase and orotidylic acid decarboxylase [127-129]. The administration of allopurinol to rats results in an increased urinary excretion of orotic acid and orotidine [127,130,131], and in elevated activities of orotate phosphoribosyltransferase and orotidylic acid decarboxylase in erythrocytes [128,129]. Also, in man, the administration of allopurinol and oxipurinol leads to an increase in the specific activity of orotate phosphoribosyltransferase and orotidylic acid decarboxylase [129]. The enzymes were found to exist in a complex as three different molecular species with molecular weights of 55000, 80000 and 113 000 daltons. The larger forms of the complex were more stable than the smaller one. In the presence of allopurinol or oxipurinol ribonucleotides (but not the corresponding free bases) the largest, most stable species predominated [129]. 

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