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. 2010 Jun 24:6:317-27.
doi: 10.2147/ndt.s9749.

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

Michael Pennick  1
Affiliations

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

Michael Pennick. Neuropsychiatr Dis Treat. .

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: ADHD; LDX; Vyvanse; absorption; lisdexamfetamine dimesylate; prodrug.

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Figures

Figure 1
Figure 1
Enzymatic conversion of LDX to active d-amphetamine. Abbreviation: LDX, lisdexamfetamine dimesylate.
Figure 2
Figure 2
Mean (SD) of systemic (A) and portal (B) plasma concentration versus time for LDX and d-amphetamine in rats. Abbreviations: LDX, lisdexamfetamine dimesylate; SD, standard deviation.
Figure 3
Figure 3
Absorption of total LDX (intact LDX and d-amphetamine) from rat intestinal segments. Abbreviation: LDX, lisdexamfetamine dimesylate.
Figure 4
Figure 4
Transport of total LDX (intact LDX and d-amphetamine) across Caco-2 cell monolayers with and without induction of PEPT1 expression. *Indicates P < 0.05 versus corresponding group without Gly-Sar added. Mean data from n = 2 or n = 3 determinations. Error bars illustrate SD except where n = 2. Abbreviations: LDX, lisdexamfetamine dimesylate; Gly-Sar, glycylsarcosine; PEPT, peptide transporter; SD, standard deviation.
Figure 5
Figure 5
Uptake of radiolabeled Gly-Sar in the presence of increasing concentration of LDX by CHO cells expressing PEPT1 (A) or PEPT2 (B). Abbreviations: LDX, lisdexamfetamine dimesylate; Gly-Sar, glycylsarcosine; CHO, Chinese hamster ovary; PEPT, peptide transporter.
Figure 6
Figure 6
LDX remaining (percentage of initial concentration) after incubation with human tissue homogenates from donors. Abbreviations: LDX, lisdexamfetamine dimesylate; t1/2, half-life.
Figure 7
Figure 7
LDX remaining (percentage of initial concentration) after incubation with blood fractions from donors. Abbreviations: LDX, lisdexamfetamine dimesylate; RBC, red blood cells; PBMC, peripheral blood mononucleated cells; PMN, polymorphonuclear cells; t1/2, half-life.
Figure 8
Figure 8
LDX remaining (percentage of initial concentration) after incubation with varying hematocrits of RBCs from a male and female donor. Abbreviations: LDX, lisdexamfetamine dimesylate; RBC, red blood cells; t1/2, half-life.
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