PHARMACOKINETICS OF 9-CIS-RETINOIC ACID IN THE RHESUS-MONKEY

9-cis-Retinoic acid is a naturally occurring biologically active retin oid capable of binding and transactivating both the retinoic acid rece ptors and the retinoid X receptors. A study was performed to character ize the pharmacokinetics 9-cis-retinoic acid following i.v. bolus admi nistration in the nonhuman primate. Groups of three animals received i .v. bolus doses of 9-cis-retinoic acid of either 50 or 100 mg/m(2). Bl ood and cerebrospinal fluid samples for determination of 9-cis-retinoi c acid concentration were obtained prior to and 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 min following drug administr ation. The plasma drug concentration profile of 9-cis-retinoic acid wa s consistent with a first-order elimination process, Kith a harmonic m ean half-life of 31 min, and a mean clearance of 97 ml/min/m(2). The p harmacokinetics of 9-cis-retinoic acid were Linear over the dose range studied. Plasma concentrations of all-trans-retinoic acid following 9 -cis-retinoic acid administration were less than the limit of quantita tion (0.1 mu M), suggesting that isomerization to all-trans-retinoic a cid is not a major metabolic pathway. In contrast to all-trans-retinoi c acid, the elimination of 9-cis-retinoic acid did not appear to be ca pacity limited (saturable). Previous studies in the Rhesus monkey have shown that repeated dosing with all-trans-retinoic acid leads to a re duction of this saturable component of elimination and results in redu ced exposure to drug. These studies, in an animal model highly predict ive of humans, suggest that declines in plasma concentrations of 9-cis -retinoic acid as a result of its repeat administration at doses up to 100 mg/m(2) will not occur.