ALL-TRANS-RETINOIC ACID PHARMACOKINETICS AND BIOAVAILABILITY IN ACUTEPROMYELOCYTIC LEUKEMIA - INTRACELLULAR CONCENTRATIONS AND BIOLOGIC RESPONSE RELATIONSHIP

Purpose: This study investigated the in vitro pharmacologic behavior a nd disposition kinetics of all-trans retinoic acid (ATRA) in acute mye loid leukemic (AML) cells, their sensitivity to its differentiating ef fect, and the in vivo response of acute promyelocytic leukemia (APL) p atients after therapy. Patients and Methods: Fresh leukemic cells from 14 AML patients (nine APL and five non-APL), were incubated in suspen sion culture in the absence or presence of 10(-6) mol/L ATRA. Intracel lular ATRA concentration and ATRA metabolism was determined by high-pe rformance liquid chromatography (HPLC). Results: Immediate uptake is o bserved with maximal intracellular levels (Cmax) achieved after 24 hou rs of incubation, At this time, ATRA levels were variable, ranging fro m 20 to 230 pmol/10(6) cells (median, 100 pmol/10(6) cells), Compariso n of ATRA intracellular levels with the in vitro response of patients' cell samples as measured by the percentage of nitro blue tetrazolium (NBT)-positive cells after a 3-day incubation period allowed us to dis criminate a group of APL patients (n = 6) with high Cmax (group A; med ian, 200 pmol/10(6) cells) and maximal differentiation at day 3 (media n, 80%), and a group of patients (n = 8, three APL and five non-APL) w ith low Cmax (group B; median, 35 pmol/10(6) cells) and poor in vitro response (median, 40%; APL cases only). Interestingly, all APL patient s, except one included in group A (rapid in vitro ATRA uptakers), achi eved a complete remission. Conclusion: These findings suggest that int racellular ATRA concentrations are determinant for ATRA response and s hould be taken into account when monitoring the efficacy of ATRA diffe rentiation therapeutic trials in malignant disorders. (C) 1995 by Amer ican Society of Clinical Oncology.