Structure-pharmacokinetics relationship of quaternary ammonium compounds

Summary Correlations between lipophilicity or molecular weight and some pharmacokinetic parameters such as clearance (Cl), elimination rate constant (k₁₀), volume of distribution (V), and terminal half life (_z) are presented for a series of structurally related quaternary ammonium cations (QACs). The structure-pharmacokinetics relations were fitted using the computer program NONLIN and were represented by linear, parabolic or S-shaped curves.The relationship between total plasma clearance or hepatic, renal and intestinal clearance and lipophilicity for the present set of data could be described most properly by the equation Y =1/(aX^b), + c),where Y stands for the logarithm of the parmacokinetic parameters and X represents the logarithm of the values of some physicochemical parameters, such as the partition coefficient (P), the (HPLC) capacity factor k (another lipophilicity parameter) and molecular weight (MW). On the basis of this relationship, correlations of the hepatic or intestinal clearances with the lipophilicity parameters were good (r-0.98 and r=0.95 respectively). Curves relating values for partition coefficients and clearance via liver and intestine (expressed relative to the most simple QAC tetramethyl ammonium) showed S-shaped correlation patterns, in contrast to the renal clearance, which correlated poorly (r=0.54) with lipophilicity. The extent of biliary output of the organic cations shows a threshold phenomenon, sharply increasing at log P>1.5 to a maximum at P>2.5. This pattern was less pronounced in the case of intestinal elimination and absent in the case of renal clearance.The apparent maximum in the hepatic and intestinal clearance for the most lipophilic organic cations is probably due to limitation by organ blood-flow and/or plasma protein binding. After correction for these factors the resulting intrinsic clearance values indicate that membrane transport in the liver and intestine but not in the kidneys will tend to increase with the lipophilicity of the organic cation.