Non-micelle forming bile acids increase biliary gentamicin excretion in the rat.
To investigate whether non-micelle forming bile acids are able to increase biliary gentamicin excretion, male Sprague-Dawley rats were anesthetized with pentobarbital and fitted with a biliary fistula. After a control period of 30 min, dehydrocholate, taurodehydrocholate, or norursodeoxycholate were administered iv at doses of 2 or 10 mumol.min-1.kg-1. Taurodehydrocholate increased bile flow and biliary gentamicin clearance similarly in a dose-dependent fashion. Its unconjugated analogue, in contrast, increased gentamicin clearance fourfold, while increasing bile flow only 1.6-fold. This suggests that other than purely osmotic phenomena were involved. This effect was even more marked for the short-chain bile acid, norursodeoxycholate. At a dose of 2 mumol.min-1.kg-1 it increased bile flow by 30%, but gentamicin clearance by 210%; a similar discrepancy between choleresis and gentamicin clearance was observed at the higher dose tested. It may be concluded that conjugated triketo bile acids increase biliary gentamicin clearance by osmotic choleresis. Unconjugated triketo bile acids and nor-bile acids, to an even greater extent, increase gentamicin clearance much more markedly than bile flow; other effects, such as the putative cholahepatic shunt pathway, are responsible for this phenomenon. This novel therapeutic principle might be useful in achieving therapeutic biliary antibiotic concentrations or in treating gentamicin intoxication in patients with renal insufficiency.
Department of Clinical Pharmacology, University of Berne, Switzerland.
R
R
Oehler
J
J
Reichen
T
T
Zysset
S E
SE
Bradley
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000494:pharmacology*; D004594:Electrophysiology; D005295:Ferrocyanides / Q000378:metabolism; D005839:Gentamicins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008823:Micelles; D010539:Permeability; D051381:Rats; D011919:Rats, Inbred Strains
D001647:Bile Acids and Salts; D005295:Ferrocyanides; D005839:Gentamicins; D008823:Micelles