Enzymatic Conversion of Lisdexamfetamine to Dextroamphetamine
Lisdexamfetamine (Vyvanse) is converted to active dextroamphetamine through enzymatic hydrolysis by aminopeptidases located in the cytosol of red blood cells, with no specific cofactors required beyond the natural enzymatic machinery present in erythrocytes. 1, 2
Enzyme and Location
The primary enzyme responsible is an aminopeptidase-like enzyme residing specifically in the cytosol of red blood cells, not in the membrane fraction or other tissues. 2
This enzymatic activity cleaves the peptide bond between L-lysine and dextroamphetamine through hydrolysis. 1, 3
The conversion occurs through rate-limited hydrolysis in the blood, which is why lisdexamfetamine provides extended-release properties compared to immediate-release amphetamine formulations. 1, 3
Cofactors and Mechanism
No external cofactors are required for this enzymatic conversion—the process relies solely on the endogenous aminopeptidase activity present in red blood cell cytosol. 2
The hydrolytic cleavage is potently inhibited by bestatin (an aminopeptidase inhibitor), protease inhibitor cocktails, and EDTA, confirming the aminopeptidase-mediated mechanism. 2
The parent drug lisdexamfetamine itself is therapeutically inactive and does not bind to norepinephrine or dopamine reuptake sites in vitro. 4, 3, 5
Clinical Pharmacokinetics
After oral ingestion, lisdexamfetamine is rapidly absorbed from the small intestine via active carrier-mediated transport, probably through peptide transporter 1 (PEPT1). 2
The enzymatic hydrolysis in red blood cells gradually releases pharmacologically active dextroamphetamine, with Tmax for dextroamphetamine occurring at approximately 3.5-4.4 hours post-dose (compared to 1 hour for the parent prodrug). 4
This rate-limited conversion provides smooth and consistent systemic delivery of d-amphetamine and contributes to the long daily duration of efficacy (up to 14 hours post-dose in adults). 2, 6
Important Clinical Implications
The prodrug design means that alternative routes of administration (injection or intranasal) do not bypass the requirement for red blood cell enzymatic conversion, contributing to lower abuse potential compared to immediate-release amphetamines. 1, 3, 5
The conversion is not dependent on gastrointestinal enzymes—while initial absorption occurs in the GI tract, the actual hydrolysis to release active dextroamphetamine occurs systemically in red blood cells. 5, 2
Food does not affect the overall exposure (AUC and Cmax) to dextroamphetamine, though it prolongs Tmax by approximately 1 hour. 4