Pharmacokinetics of all-trans-retinoic acid: clinical implications in acute promyelocytic leukemia.
Continuous daily treatment with all-trans-retinoic acid (ATRA) in patients with acute promyelocytic leukemia has been associated with a marked decline in the plasma drug concentration at the time of relapse. Recent pharmacologic studies have attempted to determine the reasons for the progressive reduction of plasma concentrations of the drug. A decrease in plasma concentrations over time may be attributed to either upregulation of metabolism or downregulation of absorption. The effect of intravenous ATRA was examined in Rhesus monkeys to help differentiate between these possibilities and to better establish the metabolism of ATRA. Findings were consistent with a capacity-limited (saturable) elimination process. A subsequent study with Rhesus monkeys demonstrated that this capacity-limited elimination process can be induced. Two potential ways of overcoming decreased plasma levels are suggested by the explanations for rapid elimination of ATRA: administration of a P-450 inhibitor such as ketoconazole to block oxidation of the drug, or use of an intermittent dosing schedule. Studies are currently under way to examine the effectiveness and tolerability of these methods.
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
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Adamson
D000818:Animals; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood* / Q000188:drug therapy; D008253:Macaca mulatta; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D014212:Tretinoin; D007654:Ketoconazole