Concentrations of N‐descyclopropyl‐methylprazepam in whole‐blood, plasma, and milk after administration of prazepam to humans

Abstract

After oral doses of 30 mg of prazepam to humans, N-descyclopropylmethylprazepam (desalkylprazepam, N-desmethyldiazepam) is the only major drug-related compound in plasma. Neither the parent drug, nor its major urinary metabolites were detected in plasma. The overall concentration-time profile of desalkylprazepam in the plasma of females was lower than, and significantly different (p less than 0.001) from that in the plasma of males. However, the mean peak desalkylprazepam concentrations in the plasma of females (265 ng ml-1 +/- 60 S.D.) were not significantly different (p greater than 0.05) from those in males (342 ng ml-1 +/- 60 S.D.). Concentrations declined in the plasma of either sex with similar half-lives (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 1.09 l h-1), range 0.74-1.84 l h-1). At 12 h after the last of multiple doses of prazepam (60 mg d-1 for 3 days) to lactating women, mean plasma concentrations of desalkylprazepam were 823 ng ml-1 +/- 200 S.D. and declined with a mean half-life of about 60 h over the time-course studied. There was only slight uptake of desalkylprazepam into blood cells; plasma; whole blood concentration ratios were constant at about 1.6. Concentrations of desalkylprazepam in milk were low at about 10 per cent of the corresponding plasma levels (e.g. 86 ng ml-1 +/- 37 S.D. at 12 h). The data suggest that, expressed on a mg kg-1 basis, exposed neonates could receive about 4 per cent of the maternal dose of prazepam as desalkylprazepam.

Pharmacokinetics of flutoprazepam, a novel benzodiazepine drug, in normal subjects

“…The early.detection of appreciable levels of this metabolite in serum and the putatively large clearance of the parent compound (inferred from its extremely low levels) suggest that dealkylation may already take place extensively during first-pass passage. The observation of secondary peaks in the N-desalkylflurazepam concentration profile is interesting, especially since a similar phenomenon has been described for N-desmethyldiazepam derived from prazepam (a benzodiazepine which is closely related to flutoprazepam structurally) (9). The decline of N-desalkylflurazepam was slow, its observed half-life (87 ± 22 h) being in good agreement with that previously reported in the literature for N-desalkylflurazepam derived from flurazepam (10,11).…”