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Biomedical subjects

R L Smith

Publications and source records attributed to R L Smith.

At least 703 records · Page 39Linked to original sources
PubMed1967

The fate of[14C]thalidomide in the pregnant rabbit.

1. The fate of [(14)C]thalidomide orally administered to pregnant rabbits at the beginning of the sensitive phase of pregnancy has been studied. 2. After the oral administration of [(14)C]thalidomide on the 192nd hour of pregnancy about 68% of the radioactivity appears in the urine and 22% in the faeces. 3. The urinary (14)C is made up as follows (% of dose): thalidomide (2); alpha-(o-carboxybenzamido)glutarimide (16); 2- and 4-phthalimidoglutaramic acids (11); 2-phthalimidoglutaric acid (0.2); 2- and 4-(o-carboxybenzamido)glutaramic acids and 2-(o-carboxybenzamido)-glutaric acid (29). 4. The plasma (14)C concentration is maximal at 12hr. after dosing and the radioactivity persists for more than 58hr. At 4hr. the main compound in the plasma is thalidomide, but its concentration steadily declines while the concentration of its hydrolysis products increases. 5. At 12, 24 and 58hr. after dosing radioactivity is present in the embryo and the maternal tissues examined. The (14)C concentration in the embryo is at nearly all times higher than that in the plasma, brain, skeletal muscle and fat but lower than that in the liver and kidney. 6. At 4hr. after dosing the mother on the tenth day of pregnancy the specific activities of the embryo and the yolk-sac fluid are similar. 7. Thalidomide is found in the embryo together with seven of its hydrolysis products for more than 24hr. after dosing. The accumulation of radioactivity in the embryo is due to retention of the polar hydrolysis products.

Adipose Tissue↗
PubMed1967

The fate of the hydrolysis products of thalidomide in the pregnant rabbit.

1. The fate in the pregnant New Zealand White rabbit of oral doses of four (14)C-labelled hydrolysis products of thalidomide, namely alpha-(o-carboxybenzamido)-glutarimide, 2-phthalimidoglutaramic acid, 2-phthalimidoglutaric acid and 2-(o-carboxybenzamido)glutaramic acid, administered on the 192nd hour of pregnancy has been studied. 2. About 60-95% of the administered (14)C of each compound appears in the urine in 58hr. and the remainder is found in the faeces and in the gut and its contents. 3. Radioactivity is present in the plasma, liver, kidney, brain, muscle, fat and embryo. 4. The (14)C-labelled substances in the plasma and embryo consist of the unchanged compounds and their further hydrolysis products. 5. Since the above four thalidomide hydrolysis products are found in the rabbit conceptus together with their further hydrolysis products after their oral administration to the pregnant rabbit, it appears that the teratogenic activity of thalidomide is due to the compound itself rather than to one or more of its hydrolysis products.

Adipose Tissue↗
PubMed1967

Biliary excretion of foreign compounds. Benzene and its derivatives in the rat.

1. The extent of the excretion in the bile of the rat of benzene and 21 of its simple derivatives was studied. 2. Some 16 compounds of molecular weight less than 200, and including neutral molecules (benzene and toluene), aromatic acids, aromatic amines and phenols, were injected in solution intraperitoneally into biliary-cannulated rats. Metabolites in the bile were identified and estimated. The extent of biliary excretion of these compounds was low, i.e. 0-10% of the dose in 24hr., and most appeared in the bile mainly as conjugates. 3. The biliary excretion of six conjugates of molecular weight less than 300, including three glycine conjugates, one sulphate conjugate, one glucuronic acid conjugate and two acetyl derivatives, was low (less than 3% of the dose). 4. It is concluded that simple benzene derivatives of molecular weight less than about 300 are poorly excreted in rat bile.

Journal Article↗
PubMed1967

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

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.

Journal Article↗
PubMed1967

Biliary excretion in foreign compounds. Sulphonamide drugs in the rat.

1. The extent of biliary excretion in the rat of 15 sulphonamide compounds was studied. 2. Most of the sulphonamides studied, with molecular weights from 172 (sulphanilamide) to 352 (N(4)-acetylsulphadimethoxine) are poorly excreted in the bile (0-4% of the dose), except sulphapyridine, sulphamethoxypyridazine and sulphadimethoxine. The last three are partly metabolized to glucuronides, whose molecular weights and polarities are such as to allow them to be excreted in the bile in appreciable amounts. 3. Succinylsulphathiazole and phthalylsulphathiazole are polar and have molecular weights (355 and 403) of an appropriate order, and are excreted unchanged in the bile in appreciable amounts. 4. Sulphadimethoxine N(1)-glucuronide (mol.wt. 487) is extensively excreted in the bile unchanged. 5. The results are examined in the light of the hypotheses put forward in the preceding paper (Millburn, Smith & Williams, 1967).

Journal Article↗
PubMed1967

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

1. The biliary excretion of injected [(14)C]aniline, [(14)C]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, [(14)C]stilboestrol glucuronide, sulphadimethoxine N(1)-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.

Journal Article↗
PubMed1967

Biliary excretion of [C]succinylsulphathiazole in the rat and rabbit.

1. After intravenous injection about 30% of the dose (20mg./kg.) of succinylsulphathiazole is excreted unchanged in the bile in 3hr. by the rat, whereas only about 1% is excreted by the rabbit. When the renal pedicles are ligated the biliary excretion of succinylsulphathiazole in the rat increases to about 80% of the dose, but in the rabbit under these conditions the biliary excretion is only 2% of the dose. 2. In the rat, the sulphonamide readily enters the liver and biliary excretion occurs against a concentration gradient from liver to bile; further, the excretory process can be saturated, and can be depressed by the simultaneous administration of phenolphthalein glucuronide or bile salts. 3. In the rabbit, these conditions have not been found; succinylsulphathiazole does not readily enter the liver from the plasma, there is no transfer of the drug from the liver cells to the bile against a concentration gradient, and no saturation or depression of the biliary excretion of succinylsulphathiazole is found. 4. It is suggested that two factors responsible, at least partly, for the low biliary excretion of succinylsulphathiazole in the rabbit are the poor entry of the sulphonamide into the liver in this species and a deficiency of the concentrative mechanism for its excretion in the bile.

Journal Article↗