Differences in the pharmacokinetic properties of orally administered all-trans-retinoic acid and 9-Cis-retinoic acid in the plasma of nude mice Journal Article
| Authors: | Achkar, C. C.; Bentel, J. M.; Boylan, J. F.; Scher, H. I.; Gudas, L. J.; Miller, W. H. Jr |
| Article Title: | Differences in the pharmacokinetic properties of orally administered all-trans-retinoic acid and 9-Cis-retinoic acid in the plasma of nude mice |
| Abstract: | 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. g-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. This effect of liarozole was reduced when a second dose of tr-RA was given 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 intermittent dosing and coadministration of inhibitors of retinoic acid metabolism. Our data also suggests that 9-cis-RA may have unique pharmacokinetic properties that warrant further investigation. |
| Keywords: | metabolism; isotretinoin; differentiation; acute promyelocytic leukemia; identification; cells; fenretinide; vitamin-a; nuclear receptor; cancer |
| Journal Title: | Drug Metabolism and Disposition |
| Volume: | 22 |
| Issue: | 3 |
| ISSN: | 0090-9556 |
| Publisher: | Williams & Wilkins |
| Date Published: | 1994-05-01 |
| Start Page: | 451 |
| End Page: | 458 |
| Language: | English |
| ACCESSION: | WOS:A1994NL97800019 |
| PROVIDER: | wos |
| PUBMED: | 8070324 |
| Notes: | Source: Wos |
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