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

Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892 [P. C. A., F. M. B., R. F. M., K. A. G., D. G. P.], and Department of Pharmacology, Cornell University Medical College, New York, New York 10021 [J. F. B., L. J. G.]

A study of chronic i.v. dosing of all-trans-retinoic acid (all-trans-RA) was performed to determine whether induction of the capacity-limited elimination process for all-trans-RA occurred with long-term drug administration. Because up-regulation of the cellular retinoic acid-binding proteins (CRABP) may act to bind all-trans-RA intracellularly, the amount of CRABP in skin biopsy samples obtained during and following the course of all-trans-RA administration was also determined. Four adult rhesus monkeys received 50 mg/m² of all-trans-RA by 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-trans-RA was characterized by a plateau phase, the duration of which decreased during the period of chronic drug administration, followed by a terminal exponential decay phase, which is consistent with a capacity-limited (saturable) elimination process. The V_max of this process increased from 0.06 µmol/min on the first day to 0.17 µmol/min by the eighth day of all-trans-RA administration, consistent with induction of an enzymatic process. The amount of CRABP measured in skin biopsy specimens was rapidly induced, increasing to approximately 3-fold baseline levels by day 3 of all-trans-RA 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-trans-RA has potential advantages over a continuous administration schedule. A period of time without drug administration 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.

¹ This work was funded in part by Grants CA43796 (to L. J. G.) and NRSA CA09251-02 (to J. F. B.).

² To whom requests for reprints should addressed, at Pediatric Branch, National Cancer Institute, Building 10, Room 13N240, 9000 Rockville Pike, Bethesda, MD 20892.

Received 11/11/92. Accepted 12/22/92.

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