Amitriptyline

Absorption	Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations occur 2-12 hours following oral or intramuscular administration.
Volume of distribution	Not Available
Protein binding	Very highly protein bound (90% or more) in plasma and tissues
Metabolism	Exclusively hepatic, with first pass effect. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline. Enzyme Metabolite Reaction Km Vmax Cytochrome P450 2D6 E-10-Hydroxyamitriptyline (E)-10-hydroxylation Cytochrome P450 2D6 Nortriptyline N-demethylation 7.12 26.7 Cytochrome P450 1A2 Nortriptyline N-demethylation 63.5 30.7 Cytochrome P450 3A4 Nortriptyline N-demethylation 70.5 53.88 Cytochrome P450 3A4 E-10-Hydroxyamitriptyline (E)-10-hydroxylation Cytochrome P450 2C9 Nortriptyline N-demethylation 50.5 71.36 Cytochrome P450 2C8 Nortriptyline N-demethylation Cytochrome P450 2C19 Nortriptyline N-demethylation 8.52 75.43 Cytochrome P450 2B6 E-10-Hydroxyamitriptyline (E)-10-hydroxylation Cytochrome P450 2B6 Nortriptyline N-demethylation
Route of elimination	Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with little unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination.
Half life	10 to 50 hours, with an average of 15 hours
Clearance	Not Available
Toxicity	LD50=350 mg/kg (in mice). Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.
Affected organisms	Humans and other mammals