Anthracenedione Antineoplastic Agent Effects on Drug Metabolism in Vitro and in Vivo: Relationship between Structure and Mechanism of Inhibition

Anthracenedione Antineoplastic Agent Effects on Drug Metabolismin Vitro and in Vivo:Relationship between Structure and Mechanismof Inhibition. KHARASCH, E. D., WENDEL, N. K., AND NOVAK, R.F. (1987). Fundam. Appl Toxicol. 9, 18–25. Two anthracenedioneantineoplastic agents, mitoxantrone and the nonhydroxylatedanalog, ametantrone, were found to inhibit hepatic microsomalcytochrome P-450-dependent drug metabolism in vitro and in vivo.Ethoxycoumarin deethylase activity of phenobarbital-inducedrabbit hepatic microsomes was inhibited 56 and 100% at 0.1 and0.5 mM mitoxantrone, respectively, whereas activity was inhibited38 and 88% at 0.1 and 0.5 mM ametantrone, respectively. Bothmitoxantrone and ametantrone were noncompetitive inhibitorsof ethoxycoumarin metabolism. Aryl hydrocarbon hydroxylase activityof hepatic microsomes was diminished 41 and 56% by 1 and 3 mMmitoxantrone, respectively; identical concentrations of ametantroneinhibited metabolism by 20 and 31%, respectively. In contrastto the inhibitory influence of both agents on monooxygenaseactivity, a differential effect on NADPH oxidation was observed.In the presence of benzo[]-pyrene, mitoxantrone enhanced microsomalNADPH oxidation by 21%, whereas ametantrone produced a 22% decreasein cofactor oxidation relative to the control rate. The anthracenedionesalso inhibited hepatic cytochrome P-450-dependent monooxygenaseactivity in vivo, as evidenced by altered hexobarbital sleeptimes of mice. Mitoxantrone (20 and 40 mg/kg) prolonged sleeptime by 59 and 68%, respectively; ametantrone (50 mg/kg) produceda 56% enhancement. These results demonstrate that both mitoxantroneand ametantrone inhibit drug metabolism in vitro and in vivo.     

An in Vitro Comparison of Rat and Chicken Brain Neurotoxic Esterase

An in Vitro Comparison of Rat and Chicken Brain Neurotoxic Esterase.NOVAK, R., AND PADLLA, S. (1986). Fundam. Appl. Toxicol. 6,464–471. A systematic comparison was undertaken to characterizeneurotoxic esterase (NTE) from rat and chicken brain in termsof inhibitor sensitivities, pH optima, and molecular weights.Paraoxon titration of phenyl valerate (PV)-hydrolyzing carboxylesterasesshowed that rat esterases were more sensitive than chicken toparaoxon inhibition at concentrations <1 µM and superimposablewith chicken esterases at concentrations of 2.5–1000 µM.Mipafox titration of the paraoxon-resistant esterases at a fixedparaoxon concentration of 100 µM (mipafox concentration:0-1000 µM) resulted in a mipafox 150 of 7.3 µM forchicken brain NTE and 11.6 µM for rat brain NTE. NTE (i.e.,paraoxon-resistant, mipafox-sensitive esterase activity) comprised80% of chicken and 60% of rat brain paraoxon-resistant activitywith the specific activity of chicken brain NTE approximatelytwice that of rat brain NTE. The pH maxima for NTE from bothspecies was similar showing broad, slightly alkaline optimafrom pH 7.9 to 8.6. [³H]Diisopropyl phosphorofluoridate (DFP)-labeledNTE from the brains of both species had an apparent mol wt of160,000 measured by sodium dodecyl sulfate polyacrylamide gelelectrophoresis. In conclusion, NTE from both species was verysimilar, with the mipafox 150 for rat NTE within the range ofreported values for chicken and human NTE, and the inhibitorparameters of the chicken NTE assay were applicable for therat NTE assay.     

Spatial orienting and focused attention in attention deficit hyperactivity disorder

Seventeen children with attention deficit disorder (ADHD) and 10 normal controls performed two tasks while event-related potentials were recorded. ADHD subjects took part in two more sessions under methylphenidate (MP) or placebo. In the spatial orienting task, invalidly cued targets elicited a longer reaction time (RT) and a P₃ that was longer in latency and greater in amplitude than did validly cued targets. Performance was similar for both groups, but the early portion of P₃ (300–400 ms) was lower in amplitude for invalidly cued targets in ADHD subjects. MP increased accuracy without affecting RT and shortened P₃ peak latency and increased the amplitude of its early portion. In the focused attention task, accuracy was greater for controls and MP, but there were no RT differenees. Attended stimuli elicited greater amplitude P₁, N₁, and P₃ than did nonattended stimuli, but these measures were unaffected by diagnosis or medication.