scholarly journals Biliary excretion in foreign compounds. Species difference in biliary excretion

1967 ◽  
Vol 105 (3) ◽  
pp. 1289-1293 ◽  
Author(s):  
M M Abou-el-Makarem ◽  
P Millburn ◽  
R L Smith ◽  
R T Williams
Keyword(s):  
Molecular Weight ◽  
Guinea Pig ◽  
Rhesus Monkey ◽  
Benzoic Acid ◽  
Biliary Excretion ◽  
Hippuric Acid ◽  
Species Differences ◽  
General Trend ◽  
Species Difference ◽  
Molecular Weights

1. The biliary excretion of injected [14C]aniline, [14C]benzoic acid, 4-amino-hippuric acid and 4-acetamidohippuric acid in six or eight species of animal (rat, dog, hen, cat, rabbit, guinea pig, rhesus monkey and sheep) was studied. 2. These compounds, with molecular weights in the range 93–236, are poorly excreted in the bile in all the species examined and, in effect, there is little significant species difference in the extent of their biliary excretion. 3. Compounds of higher molecular weight (355–495) were also studied, namely succinylsulphathiazole, [14C]stilboestrol glucuronide, sulphadimethoxine N1-glucuronide and phenolphthalein glucuronide. 4. With these compounds a clear species difference in the extent of biliary excretion was found, the rat, dog and hen being good excretors, the rabbit, guinea pig and monkey poor excretors, and the cat and sheep taking an intermediary position. 5. There was a general trend for biliary excretion to be higher in all species when the compounds were of higher molecular weight. 6. These results are discussed in their relation to species differences in drug metabolism.

scholarly journals Molecular weight as a factor in the excretion of monoquaternary ammonium cations in the bile of the rat, rabbit and guinea pig

1973 ◽  
Vol 136 (4) ◽  
pp. 967-978 ◽  
Author(s):  
Robin D. Hughes ◽  
Peter Millburn ◽  
R. Tecwyn Williams
Keyword(s):  
Molecular Weight ◽  
Bile Duct ◽  
Biliary Excretion ◽  
Guinea Pigs ◽  
Species Difference ◽  
Faecal Excretion ◽  
Molecular Weights ◽  
Pyridinium Cations ◽  
Monoquaternary Ammonium ◽  
Intact Rats

1. The excretion in the bile and urine of intraperitoneally injected14C-labelled monoquaternary ammonium or pyridinium cations was measured in bile-duct-cannulated rats (ten compounds) and in guinea pigs and rabbits (six compounds). 2. Seven of these, namely N-methylpyridinium, tetraethylammonium, trimethylphenylammonium, diethylmethylphenylammonium, methylphenyldipropylammonium, dibenzyldimethylammonium and tribenzylmethylammonium, were excreted largely unchanged in the bile and urine. 3. 3-Hydroxyphenyltrimethylammonium, 3-bromo-N-methylpyridinium and cetyltrimethylammonium were metabolized to an appreciable extent in the rat. 4. In intact rats intraperitoneally injected trimethylphenylammonium (mol.wt. 136) was excreted mainly in the urine, dibenzyldimethylammonium (mol.wt. 226) was excreted in roughly equal amounts in the urine and faeces, and tribenzylmethylammonium (mol.wt. 302) was excreted mainly in the faeces. The faecal excretion of these compounds corresponded to their biliary excretion in bile-duct-cannulated rats. About 3–4% of tribenzyl[14C]methylammonium was eliminated as14CO2. 5. In rats the extent of biliary excretion of four cations with molecular weights in the range 94–164 was less than 10% of the dose, whereas that of five cations with molecular weights 173–302 was greater than 10%. These results and other data from the literature suggested that the molecular weight needed for the biliary excretion of such cations to an extent of 10% or more of the dose was about 200±50. Studies with six cations in guinea pigs and rabbits suggest that this value applies also to these species. 6. The results suggest that the threshold molecular weight for the appreciable (>10%) biliary excretion of monoquaternary cations is different from that for anions (Millburn et al., 1967a; Hirom et al., 1972b). With rats, guinea pigs and rabbits, no significant species difference was noted, whereas with anions there is a marked species difference.

scholarly journals Species variations in the threshold molecular-weight factor for the biliary excretion of organic anions

1972 ◽  
Vol 129 (5) ◽  
pp. 1071-1077 ◽  
Author(s):  
P. C. Hirom ◽  
P. Millburn ◽  
R. L. Smith ◽  
R. T. Williams
Keyword(s):  
Molecular Weight ◽  
Guinea Pig ◽  
Urinary Excretion ◽  
Intravenous Injection ◽  
Biliary Excretion ◽  
Guinea Pigs ◽  
Organic Anions ◽  
Female Rats ◽  
Weight Factor ◽  
Molecular Weights

1. The excretion in the bile and urine after intravenous injection of 16 organic anions having molecular weights between 355 and 752 was studied in female rats, guinea pigs and rabbits. 2. These compounds were mostly excreted unchanged, except for three of them, which were metabolized to a slight extent (<7% of dose). 3. The rat excreted all the compounds extensively (22–90% of dose) in the bile. 4. In guinea pigs four of the compounds with mol.wt. 355–403 were excreted in the bile to the extent of 7–16% of the dose, four with mol.wt. 407–465 to the extent of 25–44% and eight compounds with mol.wt. 479–752 to the extent of 44–100%. 5. In rabbits four compounds with mol.wt. 355–465 were excreted in the bile to the extent of 1–8% of the dose, two compounds with mol.wt. 479 and 495 to the extent of 24 and 22%, and six compounds with mol.wt. 505–752 to the extent of 31–94%. 6. These results, together with those of other investigations from this laboratory, are discussed and the conclusion is reached that there is a threshold molecular weight for appreciable biliary excretion (i.e. more than 10% of dose) of anions, which varies with species: about 325±50 for the rat, 400±50 for the guinea pig and 475±50 for the rabbit. 7. Anions with molecular weights greater than about 500 are extensively excreted in the bile of all three species. 8. That proportion of the dose of these compounds which is not excreted in the bile is excreted in the urine, and in the three species, bile and urine are complementary excretory pathways, urinary excretion being greatest for the compounds of lowest molecular weight and tending to decrease with increasing molecular weight. 9. Some implications of this interspecies variation in the molecular-weight requirement for extensive biliary excretion are discussed.

scholarly journals The fate of benzoic acid in various species

1970 ◽  
Vol 118 (1) ◽  
pp. 47-51 ◽  
Author(s):  
J. W. Bridges ◽  
M. R. French ◽  
R. L. Smith ◽  
R. T. Williams
Keyword(s):  
Guinea Pig ◽  
Rhesus Monkey ◽  
Benzoic Acid ◽  
Urinary Excretion ◽  
Squirrel Monkey ◽  
Golden Hamster ◽  
Hippuric Acid ◽  
The Other ◽  
Main Metabolite ◽  
Fruit Bat

1. The urinary excretion of orally administered [14C]benzoic acid in man and 20 other species of animal was examined. 2. At a dose of 50mg/kg, benzoic acid was excreted by the rodents (rat, mouse, guinea pig, golden hamster, steppe lemming and gerbil), the rabbit, the cat and the capuchin monkey almost entirely as hippuric acid (95–100% of 24h excretion). 3. In man at a dose of 1mg/kg and the rhesus monkey at 20mg/kg benzoic acid was excreted entirely as hippuric acid. 4. At 50mg/kg benzoic acid was excreted as hippuric acid to the extent of about 80% of the 24h excretion in the squirrel monkey, pig, dog, ferret, hedgehog and pigeon, the other 20% being found as benzoyl glucuronide and benzoic acid, the latter possibly arising by decomposition of the former. 5. On increasing the dose of benzoic acid to 200mg/kg in the ferret, the proportion of benzoyl glucuronide excreted increased and that of hippuric acid decreased. This did not occur in the rabbit, which excreted 200mg/kg almost entirely as hippuric acid. It appears that the hedgehog and ferret are like the dog in respect to their metabolism of benzoic acid. 6. The Indian fruit bat produced only traces of hippuric acid and possibly has a defect in the glycine conjugation of benzoic acid. The main metabolite in this animal (dose 50mg/kg) was benzoyl glucuronide. 7. The chicken, side-necked turtle and gecko converted benzoic acid mainly into ornithuric acid, but all three species also excreted smaller amounts of hippuric acid.

scholarly journals The biliary excretion of anions of molecular weight 300-800 in the rat, guinea pig and rabbit

1971 ◽  
Vol 125 (2) ◽  
pp. 25P-26P ◽  
Author(s):  
F T Aziz ◽  
P C Hirom ◽  
P Millburn ◽  
R L Smith ◽  
R T Williams
Keyword(s):  
Molecular Weight ◽  
Guinea Pig ◽  
Biliary Excretion

scholarly journals Metabolism of [14C]methamphetamine in man, the guinea pig and the rat

1972 ◽  
Vol 129 (1) ◽  
pp. 11-22 ◽  
Author(s):  
J. Caldwell ◽  
L. G. Dring ◽  
R. T. Williams
Keyword(s):  
Guinea Pig ◽  
Benzoic Acid ◽  
Methyl Ketone ◽  
Species Differences ◽  
Human Subjects ◽  
Main Reaction ◽  
Unchanged Drug ◽  
Aromatic Hydroxylation ◽  
Dose Dependent ◽  
Acid Labile

1. The metabolites of (±)-2-methylamino-1-phenyl[1-14C]propane ([14C]methamphetamine) in urine were examined in man, rat and guinea pig. 2. In two male human subjects receiving the drug orally (20mg per person) about 90% of the14C was excreted in the urine in 4 days. The urine of the first day was examined for metabolites, and the main metabolites were the unchanged drug (22% of the dose) and 4-hydroxymethamphetamine (15%). Minor metabolites were hippuric acid, norephedrine, 4-hydroxyamphetamine, 4-hydroxynorephedrine and an acid-labile precursor of benzyl methyl ketone. 3. In the rat some 82% of the dose of14C (45mg/kg) was excreted in the urine and 2–3% in the faeces in 3–4 days. In 2 days the main metabolites in the urine were 4-hydroxymethamphetamine (31% of dose), 4-hydroxynorephedrine (16%) and unchanged drug (11%). Minor metabolites were amphetamine, 4-hydroxyamphetamine and benzoic acid. 4. The guinea pig was injected intraperitoneally with the drug at two doses, 10 and 45mg/kg. In both cases nearly 90% of the14C was excreted, mainly in the urine after the lower dose, but in the urine (69%) and faeces (18%) after the higher dose. The main metabolites in the guinea pig were benzoic acid and its conjugates. Minor metabolites were unchanged drug, amphetamine, norephedrine, an acid-labile precursor of benzyl methyl ketone and an unknown weakly acidic metabolite. The output of norephedrine was dose-dependent, being about 19% on the higher dose and about 1% on the lower dose. 5. Marked species differences in the metabolism of methamphetamine were observed. The main reaction in the rat was aromatic hydroxylation, in the guinea pig demethylation and deamination, whereas in man much of the drug, possibly one-half, was excreted unchanged.

scholarly journals Biliary excretion of foreign compounds. Biphenyl, stilboestrol and phenolphthalein in the rat: molecular weight, polarity and metabolism as factors in biliary excretion

1967 ◽  
Vol 105 (3) ◽  
pp. 1275-1281 ◽  
Author(s):  
P Millburn ◽  
R L Smith ◽  
R T Williams
Keyword(s):  
Molecular Weight ◽  
Bile Acids ◽  
Biliary Excretion ◽  
Polar Group ◽  
Anionic Group ◽  
Molecular Weights ◽  
Minimum Value ◽  
Conjugated Bile Acids

1. The extent of biliary excretion of biphenyl, tetralin, stilboestrol and phenolphthalein was studied in the rat. 2. Biphenyl and its 4-hydroxy and 4,4′-dihydroxy derivatives are extensively excreted in the bile as glucuronides in amounts increasing in order of molecular weight. 3. Stilboestrol and its glucuronide are excreted almost quantitatively in the bile mainly as the monoglucuronide, as are also phenolphthalein and its glucuronide. 4. Tetralin is excreted to the extent of about 13% of the dose, mainly as ac-tetralyl glucuronides. 5. The results and those of Abou-El-Makarem, Millburn, Smith & Williams (1967) are discussed and it is concluded that the extent of biliary excretion of foreign compounds in rats depends on their molecular weight and their possessing a strongly polar anionic group. There appears to be a minimum value of this molecular weight below which little biliary excretion (i.e. not more than 5–10% of the dose) occurs. There is some latitude in the choice of this molecular weight, which is about 325±50. The necessary molecular weight and polar group can be acquired by metabolism. Above this minimum value biliary excretion increases with molecular weight. It is suggested that the mechanism of the biliary excretion of foreign compounds may be similar to that of conjugated bile acids, which are highly polar and whose molecular weights exceed 400.

scholarly journals Biliary excretion of some anionic derivatives of diethylstilboestrol and phenolphthalein in the guinea pig

1977 ◽  
Vol 168 (3) ◽  
pp. 373-377 ◽  
Author(s):  
P A Barford ◽  
A H Olavesen ◽  
C G Curtis ◽  
G M Powell
Keyword(s):  
Guinea Pig ◽  
Biliary Excretion ◽  
Comparative Studies ◽  
Enzyme Activities ◽  
Species Differences ◽  
Pig Liver ◽  
Biliary Elimination ◽  
Derivatives Of ◽  
Guinea Pig Liver

The metabolic fates and modes of excretion of diethylstilboestrol mono[35S]sulphate and diethylstilboestrol di[35S]sulphate were studied in the guinea pig. Comparative studies were also made with [G-3H]diethylstilboestrol and phenolphthalein di[35S]sulphate. Diethylstiboesterol di[35S]sulphate was extensively eliminated in the bile unchanged. After administration of diethylstilboestrol mono[35S]sulphate, extensive biliary elimination of radioactivity was also recorded. Radioactive components were identified as diethylstilboestrol disulphate, diethylstilboestrol monosulphate monoglucuronide and unchanged diethylstilboestrol monosulphate. When [G-3H]diethylstilboestrol was administered, 3H-labelled diethylstilboestrol monoglucuronide, diethylstilboestrol monosulphate monoglucuronide and diethylstilboestrol disulphate appeared in the bile. Phenolphthalein di[35S]sulphate was excreted unchanged in bile. These findings are discussed in relation to studies carried out in the rat [Barford, Olavesen, Curtis & Powell (1977) Biochem. J. 164, 423–430] and species differences are related to differences in enzyme activities in rat and guinea-pig liver.

The biliary excretion of tartrazine. Sex differences in the rat and species differences in the rat, guinea-pig and rabbit

1972 ◽  
Vol 24 (1) ◽  
pp. 20-24 ◽  
Author(s):  
R. H. S. GREGSON ◽  
P. C. HIROM ◽  
P. MILLBURN ◽  
R. L. SMITH ◽  
H. B. TURBERT ◽  
...  
Keyword(s):  
Sex Differences ◽  
Guinea Pig ◽  
Biliary Excretion ◽  
Species Differences
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