Determination of (plus or minus)-1, 2-bis(3, 5-dioxopiperazinyl) propane plasma levels in rats, rabbits, and humans by GLC and mass fragmentography.

Specific assay procedures were developed to measure plasma concentrations of (plus or minus)-1, 2-bis(3, 5-dioxopiperazinyl) propane (1) by GLC using flame-ionization detection with a sensitivity limit of 5 mug/ml and by GLC-mass fragmentography with a sensitivity limit of 0.2 mug/ml. Applicability of the assay procedures was demonstrated in rats, rabbits, and humans. Plasma concentration-time curves of total 14-C activity and intact I was obtained in rats and rabbits following oral and intravenous administration of 14-C-I. Plasma elimination half-lives of I in the first 2 hr following intravenous doses in rats were 40 and 45 min in two rats. Plasma levels of I were measured over 6 hr after an intravenous dose in rabbits and followed a two-compartment open model with a terminal loglinear plasma half-life of 85 min. Significantly higher total 14-C levels compared to intact I plasma concentrations indicated rapid biotransformation in both rats and rabbits to unknown metabolites. The oral bioavailability appeared to be limited in both species relative to intravenous administration. Two patients receiving 3 g I/m-2 in tablets orally showed plasma levels of I similar to those obtained after oral doses in rats and rabbits, with peak concentrations at 2 hr after the dose (3.8 mug/ml) and with still measurable levels 12 hr after the dose (0.4 mug/ml).