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

Abstract

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.

Biliary excretion in foreign compounds. Sulphonamide drugs in the rat

“…The results obtained are considered in the light of the suggestions made in the preceding paper on the factors involved in biliary excretion. It is shown that most of the sulphonamides examined are poorly excreted in the bile and that this finding is in accord with the hypotheses elaborated by Millburn et al (1967).…”

Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships

“…These determinants are likely important for binding to transport proteins on the hepatocyte basolateral or canalicular membrane. A MW cutoff for biliary excretion was originally reported in the 1970s, with a MW threshold of 325±50 for rats and 500± 50 for humans (4,5). Based on the above threshold, it is expected that there is a higher chance for a compound with MW over 325 to undergo substantial biliary excretion (defined as >10% of the dose) in rats, while a higher MW is necessary in humans.…”

Biliary excretion of some diquaternary ammonium cations in the rat, guinea pig and rabbit

“…4. These results together with data from the literature suggest that the molecular weight at which the excretion of dications in the bile exceeds 10% of the dose is in the region of 500-600, which differs from the values for monocations (Hughes et al, 1973) and anions (Millburn et al, 1967;Hirom et al, 1972).…”

“…4. These results together with data from the literature suggest that the molecular weight at which the excretion of dications in the bile exceeds 10% of the dose is in the region of 500-600, which differs from the values for monocations (Hughes et al, 1973) and anions (Millburn et al, 1967;Hirom et al, 1972).From a study of the biliary excretion in the rat, guinea pig and rabbit of some monoquaternary ammonium or pyridinium cations, Hughes et al (1973) suggested that there is a molecular-weight threshold of about 200±50 for the significant (i.e. 10% or more of the dose) biliary excretion of monoquaternary nitrogen cations in these species.…”

“…It is ofinterest that the structure of d-tubocurarine has been questioned, and Everett et al (1970) and Codding & James (1972) Hughes et al (1973) have suggested that for the biliary excretion of monoquaternary nitrogen cations in amounts greater than 10% of the dose, the cation should have a molecular weight of not less than about 200±50. For anions this minimum molecular weight was for the rat about 325±50 (Millburn et al, 1967;Hirom et al, 1972). The data for diquaternary nitrogen cations are less extensive than for the monocations and anions, but are sufficient to make the tentative suggestion that this minimum molecular weight for dications is different from that for monocations and anions and is probably in the region of 500-600.…”