Modulation of all-trans retinoic acid pharmacokinetics by liarozole Journal Article
| Authors: | Miller, V. A.; Rigas, J. R.; Muindi, J. R. F.; Tong, W. P.; Venkatraman, E.; Kris, M. G.; Warrell, R. P. Jr |
| Article Title: | Modulation of all-trans retinoic acid pharmacokinetics by liarozole |
| Abstract: | Continuous oral dosing with all-trans retinoic acid (RA) is associated with a progressive decrease in plasma drug concentrations that has been linked to relapse and retinoid resistance in patients with acute promyelocytic leukemia (APL). Since oxidation by cytochrome P-450 enzymes is critical in the catabolism of this drug, we evaluated whether pretreatment with an inhibitor of this system, liarozole, could attenuate this phenomenon. A total of 20 patients with solid tumors completed a 4-week course of all-trans RA therapy. On days 1, 2, 28, and 29, serial plasma samples were obtained from these patients after ingestion of a single oral dose (45 mg/m2) of all-trans RA. On days 2 and 29, liarozole was given 1 h prior to ingestion of all-trans RA at single doses ranging from 75 to 300 mg. The areas under the plasma RA concentration x time curves (AUCs) were then compared in the presence and absence of pretreatment. Following continuous oral treatment, the mean day-28 AUC of all-trans RA was significantly lower than the group mean level on day 1 (504 vs 132 ng h-1 ml-1;P=0.05). This decline in plasma concentrations on day 28 was partially reversed by liarozole, which increased the mean plasma all-trans RA AUC on day 29 to 243 ng h-1 ml-1 (P=0.004). The lowest dose of liarozole that reliably produced this effect was 300 mg. No enhanced toxicity was associated with liarozole administration. We conclude that liarozole at a dose of 300 mg effectively attenuates the induced decline in all-trans RA plasma concentrations that occurs with continuous treatment. This combination may be useful in attenuating or reversing retinoid resistance. © 1994 Springer-Verlag. |
| Keywords: | clinical article; clinical trial; advanced cancer; antineoplastic agents; neoplasms; drug blood level; retinoic acid; imidazoles; pharmacokinetics; oral drug administration; tretinoin; human; priority journal; article; liarozole; support, non-u.s. gov't; support, u.s. gov't, p.h.s. |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 34 |
| Issue: | 6 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 1994-11-01 |
| Start Page: | 522 |
| End Page: | 526 |
| Language: | English |
| DOI: | 10.1007/bf00685665 |
| PROVIDER: | scopus |
| PUBMED: | 7923564 |
| DOI/URL: | |
| Notes: | Export Date: 14 January 2019 -- Article -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work