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-g p) substrates/MDR reversal agents interact with small (type 1) and bul ky (type 2) cationic drugs at the level of biliary excretion in the ra t isolated perfused liver model (IPRL). The studies were performed wit h model compounds tri-n-butylmethylammonium (TBuMA) (a relatively smal l type 1 organic cation), rocuronium (Roc) (a bulky type 2 organic cat ion) and the classical P-gp substrate doxorubicin (Dox). 2 Inhibitors were given in a 4 fold molar excess to the substrate studied. To minim ize an interaction of the substrates at the hepatic uptake level, the competing compounds were added when over 55% to 85% of the administere d 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 a nd procainamidethobromide (PAEB), both type 1 cationic compounds durin g biliary excretion. Interestingly, type 2 compounds, such as rocuroni um, clearly inhibited type 1 cationic drugs as well as Dox secretion i nto bile, whereas type 1 compounds did not significantly inhibit type 2 drug excretion into bile. The type 1 cations PAEB and TBuMA only mod erately inhibited Dox biliary excretion. Dox did not inhibit the bilia ry excretion of the type 2 agent rocuronium whereas rocuronium reduced Dox biliary excretion by 50% compared to controls. 4 MDR substrates/r eversal agents like verapamil, quinine, quinidine and vinblastine stro ngly 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 indi cate that major differences in affinity of the substrates for a single excretory system exist. Alternatively, multiple organic cation transp ort systems with separate substrate specificities may be involved in t he biliary excretion of amphiphilic drugs. Furthermore, the present st udy revealed a clear positive correlation between the lipophilicity of the potential inhibitors studied and their respective inhibitory acti vity on the biliary excretion of the model drugs investigated. 6 Our d ata are compatible with a potential involvement of P-glycoprotein in t he hepatobiliary excretion of doxorubicin as well as of some type 1 an d type 2 organic cations. Furthermore we postulate that the hydrophobi c properties of the amphiphilic cationic drugs studied play a crucial role in the accommodation of these agents by P-glycoprotein and/or oth er potential cationic drug carrier proteins in the canalicular membran e.