Time Course of Induction of Metabolism of all-fra/is-Retinoic Acid and the Up-Regulation of Cellular Retinoic Acid-binding Protein1

A study of chronic i.v. dosing of all-iranv-retinoicacid (all-frans-RA) was performed to determine whether induction of the capacity-limited elimination process for a\\-trans-RAoccurred with long-term drug admin istration. Because up-regulation of the cellular retinoic acid-binding pro teins (CRABP) may act to bind all-frans-RAintracellularly,the amount of CRABP in skin biopsy samples obtained during and following the course of all-franv-RAadministration was also determined. Four adult rhesus monkeys received 50 mg/m2of all-frans-RAby bolus i.v. injection daily for 8 consecutive days and again for one additional dose following a 7-day period without drug. The plasma disappearance curve of all-/rans-RAwas characterized by a plateau phase, the duration of which decreased during the period of chronic drug administration, followed by a terminal expo nential decay phase, which is consistent with a capacity-limited (saturable) elimination process. The Vmaxof this process increased from 0.06 umol/ min on the first day to 0.17 umol/min by the eighth day of all-irans-RA administration, consistent with induction of an enzymatic process. The amount of CRABP measured in skin biopsy specimens was rapidly in duced, increasing to approximately 3-fold baseline levels by day 3 of all-ira/iv-KA administration. It remained at this level throughout the period of chronic drug administration but diminished following the 7-day period without drug. These findings suggest that an intermittent schedule of administration for all-frans-RAhas potential advantages over a contin uous administration schedule. A period of time without drug administra tion would allow for return of plasma drug clearance toward baseline levels and down-regulation of CRABP, which could result in higher plasma drug concentrations and possibly less cytoplasmic binding of drug.