Differences in the pharmacokinetic properties of orally administered all-trans-retinoic acid and 9-cis-retinoic acid in the plasma of nude mice.
All trans-retinoic acid (tr-RA) has been used to induce leukemic cell differentiation in patients with acute promyelocytic leukemia (APL). However, the duration of remission is brief and is associated with a progressive decrease in peak plasma concentrations following chronic dosing. 9-Cis-retinoic acid (9-cis-RA) has the potential to elicit the same effects as tr-RA, because it can bind and activate the same family of nuclear receptors. It is not known whether the pharmacokinetics of this novel compound resemble those of tr-RA. In this study, we report major differences in the uptake and pharmacokinetics between orally administered tr-RA and 9-cis-RA in the plasma of nude mice. Following a single initial oral administration of either isomer, the plasma peak time of 9-cis-RA (15-30 min) occurred earlier than that of tr-RA (60-180 min), but with lower plasma concentrations and area under the concentration-time curve (AUC) value. A decrease in the AUC of plasma tr-RA was seen in animals that were given a second dose 2 days after the first dose. In contrast, an increase in the AUC of plasma 9-cis-RA was seen in animals that were given a second dose 2 days after the first dose. This increase was due to the appearance of a second 9-cis-RA peak at 180 min. When liarozole, an inhibitor of tr-RA metabolism, was coadministered with the initial tr-RA dose or a second tr-RA dose 2 weeks later, the AUC of plasma tr-RA was increased relative to tr-RA alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Achkar
C C
CC
Department of Pharmacology, Cornell University Medical College, New York, NY 10021.
Bentel
J M
JM
Boylan
J F
JF
Scher
H I
HI
Gudas
L J
LJ
Miller
W H
WH
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D007093:Imidazoles / Q000494:pharmacology; D007536:Isomerism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D012176:Retinoids / Q000097:blood / Q000493:pharmacokinetics; D014212:Tretinoin / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D014801:Vitamin A / Q000097:blood
D007093:Imidazoles; D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin; C061121:liarozole