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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY 10021.
authors.forename: V A
authors.initials: VA
authors.lastname: Miller
authors.forename: J R
authors.initials: JR
authors.lastname: Rigas
authors.forename: J R
authors.initials: JR
authors.lastname: Muindi
authors.forename: W P
authors.initials: WP
authors.lastname: Tong
authors.forename: E
authors.initials: E
authors.lastname: Venkatraman
authors.forename: M G
authors.initials: MG
authors.lastname: Kris
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy*; D014212:Tretinoin / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D014212:Tretinoin; C061121:liarozole