Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level.
1. In the present study it was tested whether known P-glycoprotein (P-gp) substrates/MDR reversal agents interact with small (type 1) and bulky (type 2) cationic drugs at the level of biliary excretion in the rat isolated perfused liver model (IPRL). The studies were performed with model compounds tri-n-butylmethylammonium (TBuMA) (a relatively small type 1 organic cation), rocuronium (Roc) (a bulky type 2 organic cation) and the classical P-gp substrate doxorubicin (Dox). 2. Inhibitors were given in a 4 fold molar excess to the substrate studied. To minimize an interaction of the substrates at the hepatic uptake level, the competing compounds were added when over 55% to 85% of the administered dose of the model compounds had been removed from the perfusate and taken up by the liver. 3. We found a mutual interaction between TBuMA and procainamidethobromide (PAEB), both type 1 cationic compounds during biliary excretion. Interestingly, type 2 compounds, such as rocuronium, clearly inhibited type 1 cationic drugs as well as Dox secretion into bile, whereas type 1 compounds did not significantly inhibit type 2 drug excretion into bile. The type 1 cations PAEB and TBuMA only moderately inhibited Dox biliary excretion. Dox did not inhibit the biliary excretion of the type 2 agent rocuronium whereas rocuronium reduced Dox biliary excretion by 50% compared to controls. 4. MDR substrates/reversal agents like verapamil, quinine, quinidine and vinblastine strongly reduced both type 1 and type 2 organic cation excretion into bile. Dox secretion into bile was also profoundly reduced by these drugs, vinblastine being the most potent inhibitor in general. 5. The lack of mutual inhibition observed in some combinations of substrates may indicate that major differences in affinity of the substrates for a single excretory system exist. Alternatively, multiple organic cation transport systems with separate substrate specificities may be involved in the biliary excretion of amphiphilic drugs. Furthermore, the present study revealed a clear positive correlation between the lipophilicity of the potential inhibitors studied and their respective inhibitory activity on the biliary excretion of the model drugs investigated. 6. Our data are compatible with a potential involvement of P-glycoprotein in the hepatobiliary excretion of doxorubicin as well as of some type 1 and type 2 organic cations. Furthermore we postulate that the hydrophobic properties of the amphiphilic cationic drugs studied play a crucial role in the accommodation of these agents by P-glycoprotein and/or other potential cationic drug carrier proteins in the canalicular membrane.
Smit
J W
JW
Department of Pharmacokinetics and Drug Delivery, Groningen Institute for Drug Studies, University of Groningen, The Netherlands.
Duin
E
E
Steen
H
H
Oosting
R
R
Roggeveld
J
J
Meijer
D K
DK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000732:Androstanols / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001659:Biliary Tract / Q000502:physiology*; D004317:Doxorubicin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000502:physiology*; D008297:Male; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077123:Rocuronium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000732:Androstanols; D000644:Quaternary Ammonium Compounds; C043902:tri-n-butylmethylammonium; D004317:Doxorubicin; D000077123:Rocuronium