Lorazepam pharmacokinetics
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Lorazepam Absorption and Bioavailability
Lorazepam is rapidly and efficiently absorbed after oral administration, with peak blood concentrations typically reached about 2 hours post-dose, and these concentrations are proportional to the administered dose Greenblatt1976Kyriakopoulos1978. After intramuscular injection, peak concentrations are achieved within 3 hours, and the absorption half-life is approximately 21 minutes . Intranasal administration also results in good absorption, with a bioavailability of about 78% and a faster absorption rate than intramuscular injection . Extended-release (ER) lorazepam formulations provide a similar overall exposure to immediate-release (IR) forms, but with a delayed peak concentration (11 hours for ER vs. 1 hour for IR) .
Distribution and Protein Binding
Lorazepam has a moderate volume of distribution, reported as 0.9 L/kg after intramuscular injection in healthy adults , and 1.5 L/kg in pediatric patients . In critically ill patients, the volume of distribution can be much higher, up to 376 L . Lorazepam is highly protein-bound in plasma, with about 83% bound in patients with renal failure .
Metabolism and Elimination
The primary metabolic pathway for lorazepam is conjugation with glucuronic acid, forming an inactive lorazepam glucuronide metabolite Greenblatt1976Kyriakopoulos1978Greenblatt1977. This glucuronide is the main form excreted in urine, accounting for 70–88% of the administered dose Greenblatt1976Kyriakopoulos1978Greenblatt1977. Other metabolites, such as hydroxylorazepam and quinazolinone derivatives, are present in much smaller amounts . The elimination half-life of lorazepam is generally around 12–14 hours in healthy adults Greenblatt1976Kyriakopoulos1978Greenblatt1977, but can be longer in pediatric patients (up to 16.8 hours) and varies with age and health status Relling1989Gonzalez2017.
Clearance and Excretion
Lorazepam is primarily cleared by hepatic metabolism, with renal excretion of the glucuronide metabolite. The renal clearance of lorazepam glucuronide is about 37 ml/min . In pediatric patients, clearance is slightly higher than in adults, but age-dependent dosing beyond a maximum initial dose is not necessary Chamberlain2011Relling1989Gonzalez2017. In patients with renal failure on continuous venovenous hemofiltration (CVVH), lorazepam itself is not efficiently removed by the procedure, but its glucuronide metabolite is cleared more effectively .
Pharmacokinetics in Special Populations
- Pediatrics: Lorazepam pharmacokinetics in children are similar to adults, with slightly higher weight-normalized clearance and a half-life ranging from 10.5 to 16.8 hours Chamberlain2011Relling1989Gonzalez2017. Uniform dosing of 0.1 mg/kg (up to 4 mg) achieves therapeutic concentrations for seizure control Chamberlain2011Gonzalez2017.
- Genetic Variability: The UGT2B15*2 genetic polymorphism significantly reduces lorazepam clearance, leading to higher drug exposure and potentially greater pharmacodynamic effects .
- Critically Ill/Renal Failure: In patients with acute renal failure, lorazepam is not efficiently removed by CVVH, but its glucuronide metabolite is .
Extended-Release and Alternative Formulations
Extended-release lorazepam provides a pharmacokinetic profile similar to immediate-release formulations given three times daily, with less fluctuation in plasma levels and similar safety . Intranasal lorazepam offers a noninvasive alternative with favorable absorption and elimination profiles .
Conclusion
Lorazepam is rapidly absorbed and extensively metabolized to an inactive glucuronide, with a typical elimination half-life of 12–14 hours in adults and slightly longer in children. Its pharmacokinetics are consistent across oral, intramuscular, intravenous, and intranasal routes, with some variability due to age, genetics, and health status. Most of the drug is excreted as glucuronide in urine, and special populations such as pediatric patients and those with renal failure may require tailored dosing or monitoring. Extended-release and intranasal formulations offer alternative delivery options with comparable pharmacokinetic profiles.
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