Vyvanse Metabolism
Vyvanse (lisdexamfetamine) does not undergo hepatic metabolism—it is converted to its active form d-amphetamine through enzymatic hydrolysis in the blood by red blood cells, not by liver enzymes. 1
Mechanism of Conversion
Lisdexamfetamine is a prodrug that is therapeutically inactive until hydrolyzed in the blood to release d-amphetamine and L-lysine, with this conversion occurring through rate-limited hydrolysis primarily by red blood cells after oral administration. 2, 1
In vitro studies demonstrated that red blood cells have high capacity for metabolism of lisdexamfetamine, with substantial hydrolysis occurring even at low hematocrit levels (33% of normal). 1
Lisdexamfetamine is not metabolized by cytochrome P450 enzymes, distinguishing it from many other medications that undergo hepatic metabolism. 1
Clinical Implications of Non-Hepatic Metabolism
The conversion is unaffected by gastrointestinal pH and variations in normal transit times, providing consistent pharmacokinetics regardless of food intake or gastric conditions. 3
This unique metabolic pathway results in a prodrug design where the parent compound does not bind to sites responsible for reuptake of norepinephrine and dopamine in vitro, with activity only occurring after blood-based conversion to d-amphetamine. 4
The rate-limited enzymatic biotransformation in blood allows for once-daily dosing with duration of activity of approximately 12-14 hours, as the conversion rate is controlled by red blood cell enzymatic activity rather than hepatic first-pass metabolism. 3, 5
Excretion Profile
Following oral administration of 70 mg radiolabeled lisdexamfetamine, approximately 96% of the dose was recovered in urine and only 0.3% in feces over 120 hours. 1
Of the urinary radioactivity, 42% was related to amphetamine, 25% to hippuric acid, and only 2% to intact lisdexamfetamine, confirming extensive conversion occurs before renal elimination. 1
The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour, while d-amphetamine half-life was 8.6-9.5 hours in pediatric patients and 10-11.3 hours in adults. 1
Drug Interaction Considerations
Because lisdexamfetamine is not metabolized by CYP450 enzymes, it avoids the substantial drug-drug interaction potential that affects medications metabolized by hepatic pathways like CYP3A4, which is responsible for metabolism of more than 50% of all drugs. 1
This non-hepatic metabolism pathway means lisdexamfetamine does not require dose adjustments for hepatic impairment and is not subject to interactions with CYP450 inducers or inhibitors that commonly affect other medications. 1