Pharmacology of N,N-di(n-butyl)adriamycin-14-valerate in the rat

Abstract

Lipophilic N-alkylanthracyclines such as AD 198 (N-benzyladriamycin-14-valerate) or AD 201 [N,N-di-(n-propyl)adriamycin-14-valerate], which exert their cytotoxicity through mechanisms which are not yet fully defined, possess inherent abilities to circumvent multidrug resistance in vitro and in vivo, possibly through alterations in normal intracellular drug trafficking. As part of structure-activity studies with this class of agent, we have now examined the pharmacology of AD 202 [N,N-di(n-butyl)adriamycin-14-valerate], another analog possessing superior antitumor activity to doxorubicin in vivo and an ability to circumvent multidrug resistance in vitro. Following the administration of AD 202 (20 mg/kg, i.v.) to anesthetized rats, rapid drug distribution (T_1/2 5 min) was followed by more gradual elimination (T_1/2 3.6 h). Plasma clearance of AD 202 (224 ± 63.6 ml/minper kg) and steady state volume of distribution (25.7 ± 11.1 I/kg) were indicative of extensive tissue sequestration and/or a large degree of extra-hepatic metabolism. The parent drug predominated in plasma until 20 min, thereafter N,N-di(n-butyl)adriamycin became the principal circulating anthracycline. The systemic exposure to this biotransformation product (area under the plasma concentration-time curve from time zero to 480 min AUC_0-480 281672 ng-min/ml) was > tenfold higher than for the other detected plasma products (N-butyladriamycin-14-valerate, N-butyladriamycin, and three unidentified fluorescent signals; PI-3). Total urinary elimination over 8 h was limited (1.9% of dose), occurring predominantly as N,N-di(n-butyl)adriamycin (1.2% of dose), N-butyladriamycin (0.4% of dose), and their corresponding 13-carbinol metabolites (< 0.1% of dose each). Low levels of adriamycin (ADR), aglycones and two unidentified products were also seen. Parental AD 202 was found in urine only up to 1 h. By contrast, hepatic elimination of parent drug was seen, albeit at low levels, through 8 h. Excretion by this route (22% of dose) occurred principally as N-butyladriamycin (8% of dose), N-butyladriamycinol (2.1% of dose) with lower levels of N,N-di(n-butyl)adriamycin (1.6% of dose), N,N-di(n-butyl)adriamycin (0.8% of dose), and aglycones (4.3% of dose, combined). Other products included ADR (1.1% of dose) and two unidentified signals (3.4% of dose, combined). The relatively poor mass balance in these studies is attributed to prolonged intracellular retention (elimination T_1/2 24.2 h) of N,N-di(n-butyl)adriamycin. Thus, in common with other N-alkylanthracyclines, the pharmacology of AD 202 is complex but its therapeutic properties clearly are not derived from an ADR prodrug effect. Significant differences continue to be noted as to the metabolic fate of congeners of this class of anthracycline analogs.