CONSTITUTIVE VARIABILITY IN THE PHARMACOKINETICS OF THE NATURAL RETINOID, ALL-TRANS-RETINOIC ACID, AND ITS MODULATION BY KETOCONAZOLE

Background: All-trans-retinoic acid (all-trans RA) induces complete re mission in most patients with acute promyelocytic leukemia (APL). Howe ver, continuous oral dosing results in progressive decline in plasma d rug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicat ing acquired resistance, resulted partly from inducible cytochrome-P45 0 oxidative enzymes, which can catabolize all-trans RA. Purpose: We st udied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P4 50 oxidative enzymes. Methods: Serial plasma samples were obtained fro m 54 patients with APL or advanced lung cancer after a single oral dos e of all-trans RA (45 mg/m2). In the 34 patients with advanced lung ca ncer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks , and, on days 2, 28, and 29, serial plasma samples were again obtaine d after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13 -cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer. Results: The mean area under the curv e for plasma drug concentration times time (AUC) for all-trans RA on d ay 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy d emonstrated significantly lower AUC levels on day 1 (P = .06); a subgr oup with levels less than 300 ng/mL per hour on day 1 had lower endoge nous plasma all-trans RA concentrations than patients with APL or earl y-stage lung cancer or 14 normal subjects. Following continuous oral t reatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P<. 01), a decline significantly attenuated by ketoconazole, which increas ed the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P <.01). Conclusion: Reported variability for the pharmacokinetics of al l-trans RA may result from disease-related or population-based differe nces in basal catabolic rates influenced by genetic or environmental f actors. However, the pattern of inducible catabolism of all-trans RA i s not disease specific. Ketoconazole attenuates this accelerated catab olism, suggesting that oxidation by cytochrome-P450 enzymes is an impo rtant pathway for both constitutive and induced pathways of all-trans RA metabolism.