Lisdexamfetamine and immediate release d-amfetamine – Differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity
Abstract
Lisdexamfetamine mesylate (Vyvanse(®)) is a novel prodrug approved for attention deficit hyperactivity disorder (ADHD). It is metabolised to d-amfetamine and l-lysine. In drug-experienced humans, lisdexamfetamine evoked lower "Drug liking" scores on Drug Rating Questionnaire (DRQ) scales than immediate-release (IR) d-amfetamine. This study investigated why lisdexamfetamine may have lower abuse potential and a better therapeutic window than d-amfetamine. We compared the pharmacokinetic/pharmacodynamic relationships of lisdexamfetamine and IR d-amfetamine in freely-moving rats by measuring simultaneously extracellular concentrations of striatal dopamine, plasma concentrations of d-amfetamine and lisdexamfetamine, and locomotor activity. At equivalent doses (1.5 mg/kg d-amfetamine base), lisdexamfetamine produced smaller, but more sustained, increases in striatal dopamine efflux than d-amfetamine and substantially less locomotor activation. Consistent with it being a prodrug, increased striatal dopamine and locomotion correlated with plasma concentration of its metabolite, d-amfetamine, but not the parent compound. Compared with IR d-amfetamine, lisdexamfetamine produced an identical AUC for plasma d-amfetamine, but a 50% lower C(max) and significantly delayed t(max). Where a hysteresis relationship did exist between plasma concentrations of d-amfetamine and striatal dopamine or locomotor activity, they were anticlockwise in direction for lisdexamfetamine and IR d-amfetamine. Fo…
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Compared with immediate-release d-amphetamine at equimolar doses, lisdexamfetamine produces an identical AUC for plasma d-amphetamine but a 50% lower Cmax and significantly delayed tmax.
“In comparison with immediate-release d-amphetamine, lisdexamfetamine produced an identical AUC for plasma d -amphetamine, but a 50% lower Cmax and significantly delayed tmax at equimolar doses (21).”
Due to its unique pharmacokinetics, lisdexamfetamine shows a lower reward property and a larger therapeutic window than d-amphetamine.
“Due to the unique pharmacokinetics, lisdexamfetamine shows a lower reward property and larger therapeutic window than d-amphetamine (21, 38).”
Rowley et al. reported that lisdexamfetamine at 1.5 mg/kg produced less locomotor activation than an equivalent dose of d-amphetamine.
“Rowley et al. (21) also reported that lisdexamfetamine at 1.5 mg/kg produced less locomotor activation than that of equivalent dose of d-amphetamine”
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Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
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“In comparison with immediate-release d-amphetamine, lisdexamfetamine produced an identical AUC for plasma d -amphetamine, but a 50% lower Cmax and significantly delayed tmax at equimolar doses (21).”
Background
- Authors
- Rowley, H. L., Kulkarni, R., Gosden, J., Brammer, R., Hackett, D., & Heal, D. J.
- Affiliations
- RenaSci (United Kingdom) (GB)
- Shire (United Kingdom) (GB)
- Corresponding author
- Heal, D.J.
- ORCID
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 63
- Issue
- 6
- Pages
- 1064-1074
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W1968014083
- Cited by
- 64
- References
- 8
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 9 · 2015: 10 · 2014: 4 · 2013: 4
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shire Pharmaceutical Research Development, UK
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- lisdexamfetamine, d-amphetamine, prodrugs, pharmacokinetic-pharmacodynamic relationship, locomotor activity, abuse liability, therapeutic window, attention deficit hyperactivity disorder, drug liking, plasma drug concentration, hysteresis
- MeSH terms
- Lisdexamfetamine Dimesylate, Central Nervous System Stimulants, Animals, Chromatography, High Pressure Liquid, Dextroamphetamine, Dopamine, Dose-Response Relationship, Drug, Indicators and Reagents, Injections, Intraperitoneal, Male, Motor Activity, Neostriatum, Rats, Sprague-Dawley, Microdialysis, Area Under Curve, Rats
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