All-trans retinoic acid (RA) induces leukemic cell differentiation and complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, remissions induced by all-trans RA tend to be brief, and relapses are associated with resistance to further treatment in vivo, although the leukemic cells appear to retain sensitivity to the cytodifferentiating effects of all-trans RA in vitro.
The clinical pharmacology of all-trans RA was examined in 13 patients with APL. The drug was administered at a constant dose of 45 mg/m2/day, given as a single dose on the first day of therapy and in two divided doses thereafter. Plasma and urinary concentrations of the parent drug and metabolites were quantitated by reverse-phase high-performance liquid chromatography and, where required, by a combination of normalphase liquid chromatography/negative chemical ionization mass spectrometry. In patients with APL, basal levels of endogenous retinol and natural retinoids were within the normal range. Peak plasma levels of all-trans RA (347 ± 266 ng/ml, mean ± SD) were reached 1–2 h after drug ingestion and decayed in a monoexponential fashion with a half-life of 0.8 ± 0.1 h. The only drug metabolite detected in plasma or urine was 4-oxo-all-trans RA (present in urine as the glucuronide conjugate). This metabolite accounted for <10% of the circulating drug in plasma, and its cumulative urinary excretion accounted for <1% of the administered dose. The drug was not found in cerebrospinal fluid.
Continued oral administration of all-trans RA was associated with a significant decrease in both the plasma peak levels and the area under the concentration-time curve (P = 0.01 and 0.004, respectively) when measured after 2–6 weeks of treatment. We previously reported that a decrease in plasma area under the concentration-time curve was highly correlated with clinical relapse. Observations in a subset of patients in this study suggested that, in fact, the major decrease occurred early, within the first 7 days of treatment. These changes were associated with a 10-fold increase in urinary excretion of 4-oxo-all-trans RA glucuronide, suggesting that the accelerated clearance from plasma was associated with increased drug catabolism.
The rapid disappearance may explain early relapse from remissions induced by all-trans RA; clinical “resistance” to all-trans RA may either wholly or in part result from an inability to sustain effective plasma concentrations of all-trans RA during continuous treatment. Induction of accelerated catabolism by a cytochrome P-450-like enzyme system could account for this phenomenon; however, alternative explanations, particularly a drug-induced increase in cellular retinoic acid-binding proteins in normal tissue, cannot be excluded. Results from this study suggest that treatment with all-trans RA in APL might be improved by discontinuous dosing schedules or by concurrent treatment with P-450 enzyme inhibitors.
Supported in part by grants FD-R-000674 from the Food and Drug Administration, and by CA-08748 and CA-05826 from the National Cancer Institute, Department of Health and Human Services. Presented in part at the annual meeting of the American Society of Clinical Oncology, May 1991.