Utilization of model compounds to evaluate effects of slight chemical modifications on their distribution. Pharmacokinetic parameters in rats and mechanisms inferred for their transmembrane transport.

The pharmacokinetics of each of the model compounds benzoylformic acid (I), p-methylbenzoylformic acid (II), p-ethylbenzoylformic acid (III), D-(-)-mandelic acid (IV), D-(-)-p-methylmandelic acid (V), D-(-)-p-ethylmandelic acid (VI), and D-(-)-p-isopropylmandelic acid (VII) were studied in rats to determine the influence of slight chemical modifications of the compounds on their distribution pharmacokinetic parameters in rats. The effects of the specific chemical modifications considered were those of the less than CHOH group of IV against the less than C=0 group of I, the para-alkylation of I and IV, and the branched alkyl group (isopropyl) against the straight chain alkyl groups of the homologs of IV. While the disappearance of I from the blood was describable by the three-compartment open model, that of IV was describable by the two-compartment open model. The apparent volume of distribution of the central compartment (V1) for IV was smaller than that for I, but the volume of the peripheral compartment (V2) for IV was greater than that (V2 + V3) for I. The disappearance of V, VI, and VII from the blood was also describable by the two-compartment open model, but the apparent V1 and V2 for these compounds were lower than those for the parent compound, IV. However, the disappearance of II and II from the blood was describable by a one-compartment open model. Evaluation of the appropriate distribution pharmacokinetic parameters suggested that the peripheral compartment for the anions of these compounds consisted of moderately perfused tissues and that the transmembrane transport of these organic anions between the central and peripheral compartments occurs by diffusion mainly through the aqueous membrane pores, which are lined with polar portions of membrane proteins and/or phospholipids. The possible increased hydrophobic bonding between the alkyl groups of these compounds and the hydrophobic groups of the proteins and/or phospholipids of the membrane pores is implicated to decrease the distribution of the para-alkylated homologs into the peripheral compartments and, consequently, diminish the volumes of their peripheral compartments. The heteroporosity of the membranes of the tissues of the central compartment is proposed as the reason for the diminished volume of the central compartment for V and VI as compared to that of IV or VII.