Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.
Cancer Res
; 53(3): 472-6, 1993 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-8381046
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tretinoína
/
Proteínas de Transporte
/
Regulação para Cima
Limite:
Animals
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
1993
Tipo de documento:
Article