title: Pharmacokinetics of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.
abstract: It has been shown that patients with acute promyelocytic leukemia (AML3 subtype) treated with all-trans retinoic acid (all-trans RA), 45 mg/m2/day, achieve complete remission through differentiation of the leukemic clone to mature myeloid cells, which die spontaneously. The pharmacokinetics of all-trans RA given by mouth were studied in 15 AML3 patients. Blood samples were drawn for 24 h following a single oral dose of 45 mg/m2 and assayed for all-trans RA and 13-cis retinoic acid (13-cis RA) plasma concentrations by specific high-performance liquid chromatography. In one patient all-trans RA and 13-cis RA levels were below the detection limits at all times. In the other patients, the time to peak concentration of all-trans RA was between 60 and 210 min (median 90 min) after ingestion, with maximum concentrations between 0.03 and 2.5 micrograms/ml (median 0.4 micrograms/ml). These concentrations were within the in vitro differentiating concentration range of all-trans RA for these patients' cells. In nine patients, enterohepatic cycling was suggested by the presence on the concentration versus time curve of a secondary peak that occurred at meal times. The apparent plasma elimination half-life was between 16.8 and 77.4 min (median 30 min). Detectable plasma levels of 13-cis RA in 12 patients indicated in vivo isomerization of all-trans RA. Despite the high inter-individual variability of all-trans RA pharmacokinetics in these patients, high blast cell counts and failure to respond to differentiation treatment tended to be associated with low all-trans RA Cmax values and high clearance estimates.
authors.affiliation: Service de Biochimie et Neurobiologie, Hôpital Saint Louis, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Lefebvre
authors.forename: G
authors.initials: G
authors.lastname: Thomas
authors.forename: B
authors.initials: B
authors.lastname: Gourmel
authors.forename: A
authors.initials: A
authors.lastname: Agadir
authors.forename: S
authors.initials: S
authors.lastname: Castaigne
authors.forename: C
authors.initials: C
authors.lastname: Dreux
authors.forename: L
authors.initials: L
authors.lastname: Degos
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
mesh_terms: D000284:Administration, Oral; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D013237:Stereoisomerism; D014212:Tretinoin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D014212:Tretinoin