Intravenous pharmacokinetics and metabolism of the reactive oxygen scavenger alpha-phenyl-N-tert-butyl nitrone (PBN) in the cynomolgus monkey.

The pharmacokinetics and metabolism of the antioxidant and reactive oxygen scavenger alpha-phenyl-N-tert-butyl nitrone (PBN) was examined in the male cynomolgus monkey after intravenous administration. Following an i.v. bolus dose of 5 mg/kg, plasma concentrations of PBN declined in a bi-exponential fashion. PBN demonstrated a moderate plasma clearance (CL(p) = 27.02 +/- 6.46 ml/min/kg) and a moderate volume of distribution at steady state (Vd(ss) = 1.70 +/- 0.23 l/kg), resulting in a terminal elimination half-life of 0.76 +/- 0.25 h. The corresponding area under the curve (AUC(0-infinity)) was 3.20 +/- 0.77 microg-h/ml. Scale-up of the in vitro microsomal intrinsic clearance data for PBN afforded a blood clearance (CLb) value of 22 ml/min/kg, which was in reasonable agreement with the observed in vivo CLb. Monkey liver microsomes catalyzed the NADPH-dependent monohydroxylation of PBN to the corresponding alpha-4-hydroxyphenyl-N-tert-butylnitrone (4-HOPBN) metabolite. The formation of 4-HOPBN and its corresponding O-glucuronide was also discernible upon qualitative analysis of pooled (0-24 h) monkey plasma and urine samples. Less than 5% of the administered dose was excreted as unchanged PBN in the urine, suggesting that P450-catalyzed metabolism constituted the major route of PBN clearance in the primate. In conclusion, the pharmacokinetic attributes and the clearance mechanism of PBN in the cynomolgus monkey is similar to that observed in the Sprague-Dawley rat.