RELATIONSHIP BETWEEN CHEMICAL-STRUCTURE AND PHYSICOCHEMICAL PROPERTIES OF SERIES OF BULKY ORGANIC CATIONS AND THEIR HEPATIC-UPTAKE AND BILIARY-EXCRETION RATES

To obtain more insight in the relationship between physicochemical pro perties of cationic drugs and their hepatobiliary transport rate, a se ries of 12 aminosteroidal neuromuscular blocking agents (NMBAs), suppl emented with data of four related NMBAs from the literature, were inve stigated in the isolated perfused rat liver. A significant correlation was found between plasma protein binding and the partition coefficien t octanol/Krebs (log P), confirming results from the literature with o ther organic cations. Evidence was found for a saturable hepatic uptak e of several NMBAs, indicating that carrier-mediated uptake processes are involved. Hepatic uptake rate was closely related to the lipophili city of the compounds; the initial extraction ratio, the apparent clea rance and the intrinsic clearance were significantly correlated to log P, We did not find a significant correlation between biliary clearanc e and lipophilicity in the current series of compounds. Pharmacokineti cs analysis of perfusate disappearance and biliary excretion data reve aled that a considerable fraction of the dose of these bulky organic c ations is stored in the liver and seems to not be directly available f or biliary excretion. This finding is in line with earlier observation s showing a pronounced accumulation of this type of compounds in mitoc hondria and lysosomes.