Pharmacokinetics of 9-c¿s-RetinoicAcid in the Rhesus Monkey

9-c/s-Retinoic acid is a naturally occurring biologically active retinola capable of binding and transactivating both the retinoic acid receptors and the retinoid X receptors. A study was performed to characterize the pharmacokinetics 9-c/s-retinoic acid following i.v. bolus administration in the nonhuman primate. Groups of three animals received i.v. bolus doses of 9-c/s-retinoic acid of either 50 or 100 mg/m2. Blood and cerebrospinal fluid samples for determination of 9-c/s-retinoic acid concentration were obtained prior to and 5, 10, IS, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 min following drug administration. The plasma drug concentra tion profile of 9-c/s-retinoic acid was consistent with a first-order elimi nation process, with a harmonic mean half-life of 31 min, and a mean clearance of 97 ml/min/m2. The pharmacokinetics of 9-c/s-retinoic acid were linear over the dose range studied. Plasma concentrations of ullfronv-retinoic acid following 9-c/s-retinoic acid administration were less than the limit of quantitation (0.1 JIM). suggesting that isomerization to all-frans-retinoic acid is not a major metabolic pathway. In contrast to ;J||-/;YIH.S -relinoic acid, the elimination of 9-c/s-retinoic acid did not appear to be capacity limited (saturable). Previous studies in the Rhesus monkey have shown that repeated dosing with all-frans-retinoic acid leads to a reduction of this saturable component of elimination and results in re duced exposure to drug. These studies, in an animal model highly predic tive of humans, suggest that declines in plasma concentrations of 9-ci'sretinoic acid as a result of its repeat administration at doses up to 100 mg/m2 will not occur.