Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine

Abstract

These studies investigated the absorption and metabolic conversion of lisdexamfetamine dimesylate (LDX), a prodrug stimulant that requires conversion to d-amphetamine for activity. Oral absorption of LDX was assessed in rat portal and jugular blood, and perfusion of LDX into isolated intestinal segments of anesthetized rats was used to assess regional absorption. Carrier-mediated transport of LDX was investigated in Caco-2 cells and Chinese hamster ovary (CHO) cells expressing human peptide transporter-1 (PEPT1). LDX metabolism was studied in rat and human tissue homogenates and human blood fractions. LDX was approximately10-fold higher in portal blood versus systemic blood. LDX and d-amphetamine were detected in blood following perfusion of the rat small intestine but not the colon. Transport of LDX in Caco-2 cells had permeability apparently similar to cephalexin and was reduced with concurrent PEPT1 inhibitor. Affinity for PEPT1 was also demonstrated in PEPT1-transfected CHO cells. LDX metabolism occurred primarily in whole blood (rat and human), only with red blood cells. Slow hydrolysis in liver and kidney homogenates was probably due to residual blood. The carrier-mediated absorption of intact LDX, likely by the high-capacity PEPT1 transporter, and subsequent metabolism to d-amphetamine in a high-capacity system in blood (ie, red blood cells) may contribute to the consistent, reproducible pharmacokinetic profile of LDX.

Keywords:

• lisdexamfetamine dimesylate
• LDX
• prodrug
• ADHD
• absorption
• Vyvanse

Acknowledgements

This research was supported by funding from Shire Development Inc. Writing and editorial assistance was provided by Susan Kralian, PhD, a former employee of Health Learning Systems and Micheal Pucci, PhD, an employee of Health Learning Systems. Editorial assistance in the form of proofreading, copy editing, and fact checking was provided by Health Learning Systems. Assays were performed at QPS, LLC, Newark, DE; Absorption Systems LP, Exton, PA; CellzDirect Inc, Austin, TX; and SOLVO Biotechnology, Budaörs, Hungary. These data were presented at the 49th Annual New Clinical Drug Evaluation Unit Meeting, June 29–July 2, 2009, Hollywood, FL.

Disclosure

The author is a full-time employee and stockholder of Shire Pharmaceutical Development Ltd.