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 remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA. PURPOSE: We studied 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-P450 oxidative enzymes. METHODS: Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, 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 obtained 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 curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, 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 increased 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 all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.

Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.

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 normal-phase 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 less than 10% of the circulating drug in plasma, and its cumulative urinary excretion accounted for less than 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of congestive heart failure on the pharmacokinetics of cibenzoline.

Six patients with chronic congestive heart failure (CHF) (New York Heart Association functional class II or III) and five healthy subjects completed this study designed to determine if CHF alters the pharmacokinetics and absolute bioavailability of cibenzoline when compared with healthy subjects. Each subject or patient was administered a one-hour intravenous infusion of 80 mg of 15N2-cibenzoline and simultaneously received an 80-mg oral dose of cibenzoline that allowed for analytic separation of each route of administration. Resulting plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for cibenzoline. There were no statistically significant differences in any pharmacokinetic parameter between patients with CHF and healthy subjects. The absolute bioavailability ranged from 74% to 97% in those with CHF. The volume of distribution following the intravenous dose ranged from 3.4 to 6.1 L/kg, and plasma clearance ranged from 245 to 642 mL/min, with an apparent elimination half-life of approximately ten hours. Approximately 60% of the dose was recovered in the urine. Overall, the pharmacokinetics of cibenzoline in patients with chronic CHF do not differ from those observed in healthy subjects.

The effect of the cytochrome P-450 suicide inactivator, 1-aminobenzotriazole, on the in vivo metabolism and pharmacologic activity of flurazepam.

Flurazepam (F) is an extensively prescribed hypnotic (Dalmane) whose in vivo activity has been suggested to be due to its primary metabolites, hydroxyethyl flurazepam (HEF) and N-desalkylflurazepam (DAF). In order to determine the intrinsic pharmacologic activity of F, mice were administered various doses of the cytochrome P-450 suicide inactivator, 1-aminobenzotriazole (ABT), 1 hr before the ip administration of 1 mg/kg 14C-F. One hr after 14C-F, 70 mg/kg pentylenetetrazole was administered iv and the mice were observed for convulsions. F alone offered no protection from convulsion (mean brain concentrations were 3.9, 32, and 11 ng/g for F, DAF, and HEF, respectively). F with 25 mg/kg ABT also offered no protection despite a 6-fold increase in brain concentrations of F. F with 100 mg/kg ABT offered a 57% protection from convulsions (mean brain concentrations were 99, 62, and 41 ng/g for F, DAF, and HEF, respectively). One mg/kg F with 400 mg/kg ABT offered 100% protection from convulsions (brain concentrations were 190, 47, and 18 ng/g for F, DAF, and HEF, respectively). These data indicate that F has intrinsic pharmacologic activity which must be considered when evaluating the pharmacodynamics of F.