Biliary excretion species differences

Tlie approacli in tliis chapter is to consider first the chemical and then tile biological factors in the biiiary excretion of organic compounds. The types of compound excreted in the bile will be discussed from the point of view of relating eiiemieal structure to biliary excretion. One important biological factor is metabolism, because most substances undergo metabolic cliange in the body, and for certain compounds, this produces metabolites ivith the necessary structural factors for extensive biliary excretion. Species differences in biliary excretion are then de.scribed, and finally, some po.ssible reasons for these differences are discussed. 

Species differences in the metabolism of propachlor are summarized in Table II. All species studied metabolized propachlor in the MAP. Obvious, but unexplained differences are that the rat excreted no cysteine conjugate and the chicken formed no methylsulfonyl-containing metabolites. The absence of methylsulfonyl formation by chickens is thought due to the low biliary secretion of first pass metabolites. The ruminant (sheep) excreted large amounts of cysteine conjugate in urine which is also not explained. We do not know if the intestinal flora are involved in the formation of the methylsulfonyl acetanilides isolated from sheep urine. 

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). 

The species pattern of the rabbit and the guinea pig being poor biliary excretors and the rat being an extensive biliary excretor is maintained with many other compounds. With compounds of higher molecular weight, however, species differences are less, as illustrated by the compound indocyanine green (Table 5.8). The metabolism of a compound obviously influences the extent of biliary excretion, and therefore species differences in metabolism may also be a factor. 

A recent example of a species difference in metabolism causing a difference in toxicity is afforded by the alicyclic hydroxylation of the oral antiallergy drug, proxicromil (Fig. 5.11). After chronic administration, this compound was found to be hepatotoxic in dogs but not in rats. It was found that dogs did not significantly metabolize the compound by alicyclic oxidation, whereas rats, hamsters, rabbits, and man excreted substantial proportions of metabolites in the urine. In the dog, biliary excretion was the route of elimination of the unchanged compound,... 

Why does the biliary excretion of chemicals differ between different species ... 

Abou-EI-Makarem MM, Millburn P, Smith RL, et al. Biliary excretion in foreign compounds. Species difference in biliary excretion. Biochem J 1967 105 1289-1293. 

The degree of biliary excretion is species dependent. Generally, mice, rats, and dogs have a better biliary excretion than rabbits, monkeys, and humans [118]. Gd-BOPTA has a 0.6 % biliary excretion in humans, the remainder being excreted in urine [119]. Gd-EOB-DTPA has a biliary excretion of 43.1-53.2%, a renal excretion of 41.6-51.2%, and an extrahepatic recirculation of about 4% in humans [120]. In various animals, excretion is slightly different. For example, the biliary excretion of Gd-BOPTA in rats is 55% and in rabbits is 25% [121], Gd-EOB-DTPA has a 63-80% biliary excretion in rats and a 32-34% excretion in monkeys [122]. 

The tetracyclines, apart from doxycycline and minocycline, are slowly eliminated by renal excretion (glomerular filtration). Their slow elimination can be attributed to enterohepatic circulation whereby drug excreted by the liver in bile is reabsorbed from the intestine. The half-life of oxytetracycline differs widely between animal species goat (3.4 h), cattle (4.0 h), sheep (5.2 h), dog (6.0 h), pig (6.0 h), donkey (6.5 h), horse (9.6 h), and red-necked wallaby (.Macropus rufogriseus) (11.4 h). Doxycycline, unlike other tetracyclines, is eliminated by biliary excretion and diffusion into the intestine. The half-life of doxycycline is relatively short in dogs (7.0 h) and cats (4.6 h) compared with human beings (16 h). The half-life of doxycycline in chickens (4.8 h) is shorter than in turkeys (10 h) (Santos et al, 1996). Minocycline is mainly eliminated by hepatic metabolism. 

Recently Mrp2 knockout mice have been established and we can directly evaluate the role of Mdrl, Mrp2, and Bcrp in pharmacokinetics of drugs in mice without considering the species difference in rat and mouse Mrp2 when using EHBRs or GY/TR- rats [84]. Previous reports have demonstrated the biliary excretion of... 

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. 

The rate of bile secretion and the pH of the bile may also be determinants of the extent of biliary excretion of a foreign compound, and these also show species variations. The fate of compounds excreted in the bile may also depend on the species, as differences in intestinal pH and flora occur. A particularly important consequence of biliary excretion is metabolism by the gut flora and reabsorption. This enterohepatic circulation prolongs the length of time the animal is exposed to the foreign compound, and may introduce novel toxic metabolites. This could therefore result in marked species differences in toxicity. 

Naganuma A, Imura N (1984b) Species differences in biliary excretion of methyl-mercury. Biochem Pharmacol 33 679-682... 

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