Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.
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 Vmax of this process increased from 0.06 mumol/min on the first day to 0.17 mumol/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.
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
P C
PC
Adamson
J F
JF
Boylan
F M
FM
Balis
R F
RF
Murphy
K A
KA
Godwin
L J
LJ
Gudas
D G
DG
Poplack
D000818:Animals; D001706:Biopsy; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D018168:Receptors, Retinoic Acid; D012867:Skin / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D002352:Carrier Proteins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin