Clonazepam pharmacokinetics, brain uptake, and receptor interactions.

The 7-nitrobenzodiazepine derivative clonazepam is initially biotransformed by nitroreduction, followed by acetylation. Neither the amino- nor the acetamido- metabolites appear to have important pharmacologic activity. Clonazepam elimination half-life falls in the range of 20 to 80 hours, but means within the population and variance are not well defined. Absorption of orally administered clonazepam is 80% or more. In experimental studies, clonazepam appears to diffuse passively from plasma into brain, with a constant brain-plasma concentration ratio. The drug disappears in a parallel fashion from both brain and plasma, with no evidence of sequestration in brain tissue. Clonazepam has a relatively high molar affinity for the benzodiazepine receptor in vitro, and the fractional extent of benzodiazepine receptor occupation by clonazepam in vivo is directly and predictably related to the drug's concentration in brain tissue. Acute behavioral effects are in turn directly related to the extent of receptor occupancy. Compared to other benzodiazepines, the reportedly unique clinical properties of clonazepam are neither associated with unusual/unexpected pharmacokinetic properties or with a qualitatively different in vivo interaction with the presumed benzodiazepine binding site.