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). H owever, the duration of remission is brief and is associated with a pr ogressive decrease in peak plasma concentrations following chronic dos ing. g-Cis-retinoic acid (9-cis-RA) has the potential to elicit the sa me 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 ad ministered tr-RA and 9-cis-RA in the plasma of nude mice. Following a single initial oral administration of either isomer, the plasma peak t ime of 9-cis-RA (15-30 min) occurred earlier than that of tr-RA (60-18 0 min), but with lower plasma concentrations and area under the concen tration-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 fir st dose. In contrast, an increase in the AUC of plasma 9-cis-RA was se en in animals that were given a second dose 2 days after the first dos e. This increase was due to the appearance of a second 9-cis-RA peak a t 180 min. When liarozole, an inhibitor of tr-RA metabolism, was coadm inistered with the initial tr-RA dose or a second tr-RA dose 2 weeks l ater, the AUC of plasma tr-RA was increased relative to tr-RA alone. T his effect of liarozole was reduced when a second dose of tr-RA was gi ven 2 days after the first dose. Liarozole exerted its greatest effect on this second peak of 9-cis-RA. These results support the idea that higher plasma concentrations of tr-RA might be achieved through interm ittent dosing and coadministration of inhibitors of retinoic acid meta bolism. Our data also suggests that 9-cis-RA may have unique pharmacok inetic properties that warrant further investigation.