TIME-DEPENDENT DISPOSITION OF BETA-NAPHTHOFLAVONE IN THE RAT

The pharmacokinetics of beta-naphthoflavone (BNF) have been investigated in rats following various modes of intravenous administration. From intravenous bolus studies it was established that BNF showed a high blood clearance (130 ml/min/kg) and no detectable excretion of unchanged compound in the urine. The volume of distribution for BNF was large (6 L/kg), and binding to plasma proteins extensive (96%). Intravenous infusion studies where the length of infusion was increased from 1 to 8 hr showed marked signs of time-dependent pharmacokinetics. During continuous infusions the plasma concentrations accrued for approximately 1 hr. after which plasma concentrations declined in an apparent exponential fashion to a plateau value. In the short infusion studies the postinfusion half-life (27 min) was significantly shorter than the terminal half-life after bolus administration (40 min). Time-dependent clearance of BNF resulting from enhancement/induction of P450IA enzymes is proposed as the mechanism for these unusual pharmacokinetic features. The use of antipyrine as an independent probe for P450 activity gave similar trends in antipyrine clearance for various modes of BNF administration. Computer simulations based on an autoinduction model for time-dependent clearance were consistent with the observations on BNF in the rat.