Pharmacokinetic Properties

Absorption.

Diazepam is rapidly and completely absorbed from the gastrointestinal tract, with peak plasma concentrations appearing 30-90 minutes after oral intake. Buy Valium Roche diazepam 10mg online Australia
Following daily dosing, diazepam levels reach a steady state within approximately 5 days; it takes about twice as long before desmethyl diazepam levels reach a steady-state. Average steady-state levels of diazepam after once daily administration are approximately twice as high as the peak levels of the drug after the first dose.
During treatment, the elimination half-life of diazepam may increase by 50% due to a reduction in hepatic clearance. Reports on the evolution of plasma levels during long-term treatment are conflicting. A strong decrease in diazepam levels during long-term treatment, possibly due to metabolic auto-induction, has been found, but in other studies plasma concentrations of both diazepam and its desmethyl metabolite were independent of duration of therapy. Buy Valium Roche diazepam 10mg online Australia

Distribution.

The volume of distribution at steady state averages between 0.88 and 1.1 L/kg when derived from plasma concentration measurements. Both protein binding and volume of distribution of desmethyldiazepam are similar to those of diazepam.
The high protein binding limits the extent of diazepam uptake into the cerebrospinal fluid (CSF). CSF levels in man following single and multiple doses approximate closely the free drug concentration in plasma. Upon multiple dosing desmethyldiazepam, but not diazepam, may significantly accumulate in CSF. Diazepam has very rapid uptake into and equilibration with brain tissue, with equilibrium concentrations in brain exceeding those in plasma. The overall time-course of receptor occupancy was consistent with the time-course of the sum of brain concentrations of diazepam plus metabolites. Buy Valium Roche diazepam 10mg online Australia

Metabolism.

Diazepam is metabolised to pharmacologically active metabolites such as desmethyldiazepam, a pathway accounting for 50-60% of total diazepam clearance; 3-hydroxylation (27% of total diazepam clearance) is slow, leading to only low plasma levels of the oxidation products temazepam and oxazepam. Oxazepam and temazepam are further conjugated to glucuronides.
Oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyldiazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolisers (EMs), and poor metabolisers (PMs) of diazepam can be distinguished. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose. Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyldiazepam. There appear to be inter-ethnic differences in this polymorphism. Buy Valium Roche diazepam 10mg online Australia

Excretion.

The plasma concentration-time curve of diazepam is biphasic; an initial rapid and extensive distribution phase being followed by a prolonged terminal elimination phase. Typical elimination half-life values are in the range of 24-48 hours for diazepam and 40-100 hours for the active metabolite desmethyldiazepam. The clearance of diazepam is 20-40 mL/min.
Only insignificant amounts of unchanged diazepam are eliminated indicating that the drug is almost completely metabolised before leaving the body. Oxazepam-glucuronide is the main drug-related product in urine. Buy Valium Roche diazepam 10mg online Australia