Gastrointestinal radiology. Pharmacokinetics of iopanoate and iodoxamate in rhesus monkeys.

The pharmacokinetics, biliary excretion, plasma protein binding, enterohepatic circulation, and biotransformation of iopanoic acid and iodoxamic acid in the rhesus monkey were evaluated by a dynamic infusion method. The dynamic method has the advantage that the pharmacokinetic parameters involved in the hepatic uptake and biliary excretion can be evaluated from a single infusion experiment. The percentage of iodoxamic acid not bound to plasma protein varied from 6.1-41.2% as iodoxamic acid plasma levels were from 42 microM to 912 microM. Using the Freundlich isotherm approach, more than one class of binding site for iodoxamic acid was found. A saturable biliary excretion mechanism or hepatic uptake mechanism was determined with a Vmax of 1.03 microM/kg/min. Less than 1% of iodoxamic acid injected into the duodenum was recovered in the bile in 12 hours. Iodoxamic acid was found to exist in blood as an unchanged species. Iopanoic acid was extremely highly bound to monkey plasma protein. As blood concentration increased from 18.9 to 464 microM, the percentage unbound in plasma protein varied from 0.1-2.8%. Biliary excretion rates of iopanoic acid were fitted by a computer to the Michaelis-Menten equation against unbound plasma concentration and the average Vmax value was found to be 0.85 microM/kg/min with an average Kmax value of 0.253. Iopanoic acid was found to exist in monkey blood as unchanged species and in the bile mainly as an ester glucuronide. Coadministration experiments revealed that the interaction of iodoxamic acid and iopanoic acid in the monkey is complex. The compounds appear to compete for plasma protein binding sites as well as for binding sites on intrahepatic protein. The biliary excretion data seem to fit the ligant exclusion model, in which iopanoic acid acts as an inhibitor and competes with iodoxamic acid for binding to either of two identical sites in the liver, which, presumably, is the rate-limiting step in the liver's overall elimination of these radiographic agents.