Physiologic pharmacokinetic model of iopanoic acid metabolism in rats.

The kinetics of iopanoate metabolism have been examined using a physiologic and pharmacokinetic model in rats. The kinetics of iopanoic acid concentration in blood and in eight other major tissue distribution compartments have been determined and fitted to computer-generated concentrations based on a well-established pharmacokinetic model. The results of these studies in nonfasted, conscious rats revealed that after gastric administration of the contrast material tissue concentrations never exceed 30 microgram/g even in the liver. In addition, a clear-cut enterohepatic circulation of the drug was noted in the experimental setting and had to be incorporated into a computer-generated model to account for differences in the predicted model as compared to the experimental data. Such data point out the importance of knowledge of pharmacokinetics of a drug for development of more appropriate dosage regimens of older compounds, theoretical design and testing of new compounds, or to explain clinically observed drug-related phenomenon.

Binding of iophenoxate and iopanoate to human serum albumin.

Determination of the binding affinities of 125I-labeled cholecystographic agents to human serum albumin by ultrafiltration techniques is complicated by the appearance of radiochemical impurities resulting from radiolysis of the parent compound. With labeled compounds purified daily by two extractions through chloroform, iophenoxic acid has an extremely high binding affinity. The dissociation constant (K) is 0.013 micronM for iophenoxate, compared to 0.15 micronM for iopanoate, its close analogue. However, at the weaker sites, iophenoxic acid is less strongly bound than iopanoate. The exceptionally high affinity of iophenoxate for a single site of serum albumin appears to underlie its unusual persistence in plasma. Binding in vivo is reversible and not covalent in nature. The choleretic compounds cinchophen and taurocholate have differential effects on the biliary excretion of iophenoxate and iopanoate. This cannot be attributed to selective inhibition of binding to plasma protein.

Competition for binding to multiple sites of human serum albumin for cholecystographic agents and sulfobromophthalein.

The binding of two cholecystographic agents, iophenoxate and iopanoate, to human serum albumin was studied with 11 putative competitors; the results were qualitatively consistent with competitive binding to common sites. A more precise analysis of competition was achieved with four pairs of compounds for which the free and bound concentration of each was determined. The results were analyzed by a computer program and the dissociation constants calculated for both binder and competitor at specified sites on albumin. With numbering based on the rank order of dissociation constants for iophenoxate, the highest binding of the four compounds occurs at different sites: iophenoxate at site I; iopanoate at site II, sulfobromophthalein at site III; and bromphenol blue at site II. For a given compound, there is close agreement in the calculated affinities at different sites regardless of the competitor.

The interaction of iopanoic and iophenoxic acids with human serum albumin.

Iopanoic and iophenoxic acids are strongly bound to human serum albumin, as revealed from ultracentrifugation experiments. About two or three high affinity binding sites were found for both drugs. Within the concentration range investigated iopanoic acid is stronglier bound than iophenoxic acid. The binding to only one of the high affinity binding sites produces extrinsic Cotton effects. Further saturation of the high affinity binding sites decreases the extrinsic Cotton effects, possibly due to a binding induced change of the protein conformation.

Biliary excretion of iopanoate glucuronide by the rat.

Biliary excretion, plasma decay, and tissue distribution of 125I after a single intravenous dose (13 mumol/kg) of 125I-Iopanoate and 125I-iopanoate glucuronide were compared in control and phenobarbital-pretreated rats under either anesthesia. In control animals the plasma decay of iopanoate glucuronide following iopanoate glucuronide administration was significantly greater than that after iopanoate administration. Biliary clearance following iopanoate glucuronide was approximately 20 times greater than that after iopanoate; within 60 min, 82% of the dose of iopanoate glucuronide, compared to 23% of the dose of iopanoate, was recovered in bile. Phenobarbital pretreatment significantly increased the biliary excretion following iopanoate administration but had no effect on that following iopanoate glucuronide. The urinary excretion after both agents was less than 3% of the administered dose within the 60-min experimental period. The data suggest that intracellular metabolism and/or binding may account for the marked difference in the biliary excretion of iopanoate glucuronide following iopanoate as compared to that after administration of iopanoate glucuronide.

Saturation kinetics of iopanoate in the dog.

Experiments were carried out in dogs with a modified Thomas cannula in the duodenum through which the common bile duct could be catheterized. Constant intravenous infusion of sodium iopanoate at different infusion rates greater than the apparent excretion maximum revealed linearity of the blood concentration with time above a threshold concentration. When the slopes of the blood curves were plotted against the known infusion rates, a straight line relationship was obtained. The X axis intercept of this straight line represents an apparent transport maximum. This value obtained from the X axis intercept matched closely with the observed excretion maximum determined from bile and urine collection. The slope of this same line equals the inverse of the volume of distribution of the drug. Although previous workers have failed to appreciate an apparent transport maximum for iopanoate, the current studies clearly demonstrate that iopanoate is excreted by a saturable mechanism. Using this technique the apparent transport maximum for iopanoate was evaluated at high and low rates of taurocholate replacement to evaluate the quantitative effect of bile salt on the apparent transport maximum. A five-fold increase in taurocholate replacement led to an average 40% increase in the apparent transport maximum of iopanoate without effecting its volume of distribution significantly.