Effects of colchicine on the maximum biliary excretion of cholephilic compounds in rats.
OBJECTIVE
Colchicine, an inhibitor of intracellular vesicular transport, has been reported to inhibit the biliary excretion of bile acids and organic anions, but the previous findings are controversial. In order to systematically evaluate the effect of colchicine on the biliary excretion of cholephilic compounds, we studied the effect of colchicine on the biliary excretion of substrates of various canalicular transporters, which were administered at or above the excretory maximum in rats.


METHODS
Substrates of various canalicular adenosine triphosphate-binding-cassette transporters were infused at or above the rate of maximum excretion into rats, and the effect of colchicine (0.2 mg/100 g), which was intraperitoneally injected 3 h before, on the biliary excretion was studied. Furthermore, the effect of tauroursodeoxycholate (TUDC) co-infusion on the biliary excretion of taurocholate (TC) after colchicine treatment was also studied.


RESULTS
The biliary excretion of TC and cholate administered at the rate of 1 micro mol/min/100 g was markedly inhibited by colchicine, whereas that of TUDC was not inhibited even with the infusion rate of 2 micro mol/min/100 g. TUDC co-infusion at the rate of 1 micro mol/min/100 g increased the biliary excretion of TC (1 micro mol/min/100 g), which was decreased by the colchicine pretreatment. The biliary excretory maximum of taurolithocholate-sulfate and sulfobromophthalein, substrates of the multidrug resistance protein 2, of erythromycin, a substrate of the P-glycoprotein, and of indocyanine green were not affected by colchicine.


CONCLUSIONS
The different excretory maximums of TC and TUDC and the different effect of colchicine on the excretion of these bile acids are considered to be a result of different regulatory mechanisms of vesicular targeting of the bile salt export pump to the canalicular membrane by these bile acid conjugates. The vesicular targeting of the multidrug resistance protein 2 and the P-glycoprotein to the canalicular membrane is considered to be colchicine insensitive in the absence of bile acid coadministration.
Tachizawa
Hidetaka
H
Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Sano
Naoyo
N
Takikawa
Hajime
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology*; D004917:Erythromycin / Q000493:pharmacokinetics; D007208:Indocyanine Green / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D013655:Taurochenodeoxycholic Acid / Q000493:pharmacokinetics; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D013658:Taurolithocholic Acid / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D013448:Sulfobromophthalein; D013655:Taurochenodeoxycholic Acid; D013658:Taurolithocholic Acid; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D004917:Erythromycin; D007208:Indocyanine Green; D003078:Colchicine