Biliary excretion of drugs: role of ligandin in newborn immaturity and in the action of microsomal enzyme inducers.
Microsomal enzyme inducers such as phenobarbital, spironolactone and pregnenolone-16alpha-carbonitrile increase the rate of disappearance of drugs such as sulfobromophthalein and ouabain, from the plasma, to a similar extent by increasing their rate of excretion into bile. However, this effect is not observed after 3-methylcholanthrene. The enhanced biliary excretion is not dependent on increased biotransformation only, since ouabain is not biotransformed before excretion. Newborn rats are immature in their ability to excrete drugs such as BSP and ouabain. Since a hepatic cytosol protein, ligandin, has been shown to bind many drugs and is suggested to be important in the hepatic removal of drugs from the plasma, the correlation between the hepatic content of ligandin and hepatic excretory function was measured. Treatment of adult rats for 4 days with phenobarbital increased the amount of ligandin by 85%, whereas spironolactone increased it by 35% and 3-methylcholanthrene by 17%. The amount of ligandin in the livers of 5-day-old rats was about 10% that of adults and increased until the rats were about 35 days of age. Althoughh ligandin bound sulfobromophthalein, it did not bind ouabain. Since little correlation between the ability of microsomal enzyme inducers to increase ligandin and to increase biliary excretion exists, and since ouabain is excreted at a faster rate after administration of microsomal enzyme inducers and at a slower rate in newborn rats, even thoug ligandin does not bind ouabain, it is suggested that the amount of ligandin in the liver is not related to the increased biliary excretion after micromomal inducers, nor to the decreased hepatic excretory function in newborn rats.
D000375:Aging; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002352:Carrier Proteins / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D010042:Ouabain / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013448:Sulfobromophthalein / Q000378:metabolism; D013997:Time Factors
D002352:Carrier Proteins; D013448:Sulfobromophthalein; D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D010042:Ouabain; D005982:Glutathione Transferase; D010634:Phenobarbital