Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: A novel d-amphetamine pro-drug

Lisdexamfetamine is enzymatically hydrolyzed by an erythrocyte peptidase to yield d-amphetamine, the active metabolite.

“Hutson et al. reported that the pharmacodynamic effects of lisdexamfetamine are independent of the route of administration (20), which is enzymatically hydrolyzed by an erythrocyte peptidase (the rate-limiting step) to yield d-amphetamine, the actual pharmacological active metabolite.”

The pharmacodynamic effects of lisdexamfetamine are independent of the route of administration.

“Hutson et al. reported that the pharmacodynamic effects of lisdexamfetamine are independent of the route of administration (20), which is enzymatically hydrolyzed by an erythrocyte peptidase (the rate-limiting step) to yield d-amphetamine, the actual pharmacological active metabolite.”

LDX remains pharmacologically inactive until an enzymatic process predominantly associated with red blood cells converts it to the active ingredient d-amphetamine and the amino acid lysine.

“Due to its long-acting properties, LDX remains pharmacologically inactive until an enzymatic process predominantly associated with red blood cells converts it to the active ingredient, d-amphetamine and the amino acid lysine.”

LDX is a water-soluble prodrug of the single isomer d-amphetamine and l-lysine that remains pharmacologically inactive until enzymatic hydrolysis predominantly by red blood cells converts it to d-amphetamine.

“Lisdexamfetamine dimesylate is a water-soluble prodrug of the single isomer—d-amphetamine and l-lysine—that remains pharmacologically inactive until it undergoes enzymatic hydrolysis predominantly by red blood cells converting the pharmacologically inactive molecule to the active drug moiety, d-amphetamine.”

In one in vitro study, LDX biotransformation is unaffected in sickle cell pathology.

“one in vitro study noted that the biotransformation is unaffected in sickle cell pathology”

LDX modulates seven human protein targets: it activates TAAR1 and inhibits SLC18A2, DAT, NET, SERT, MAOA, and MAOB.

“LDX has been reported to modulate with pharmacological action of seven human protein targets (Table 2). On the one hand, it acts as activator of TAAR1. On the other hand, six protein targets are inhibited by LDX: synaptic vesicular amine transporter (SLC18A2), DAT (SLC6A3), NET (SLC6A2), SERT (SLC6A4) and amine oxidase [flavin-containing] (MAO) A and B [153–157].”

The active form of LDX (d-amphetamine) has central nervous system stimulating activity by primary inhibition of DAT, NET, TAAR1 and VMAT2, among other targets, thereby regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft.

“The active form of the drug has a central nervous system stimulating activity by the primary inhibition of DAT, NET, trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (SLC18A2), among other targets, therefore regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft [153].”

Both drugs promote the activation of DRD1, DRD5, ADRA2A and ADRA2B, modulating dopaminergic and adrenergic signalling, thereby regulating reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft.

“Regarding the indirect drug-induced molecular changes, both drugs promote the activation of DRD1, DRD5, ADRA2A and ADRA2B, then modulate the dopaminergic and adrenergic signalling, therefore regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft [131, 153].”

Another target protein activated by LDX is SLC18A2 (VMAT2) that contributes to regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft.

“Another target protein activated by LDX is SLC18A2 (also known as VMAT2) that contributes to regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft [153].”

MPH and LDX have similar targets and act in the same way: both promote the inhibition of DAT and NET.

“MPH and LDH have similar targets and act in the same way: both promote the inhibition of DAT and NET [153, 156, 157].”

All of these targets are involved in presynaptic signalling, and LDX therefore has a role in regulating three main NT pathways: DA, NE and serotonin.

“All of these targets are involved in the presynaptic signalling, and LDX therefore has a role in regulating three main NT pathways: DA, NE and serotonin.”

LDX inhibits DAT and NET transporters leading to an increase in DA and NE levels in the synaptic cleft.

“LDX inhibits DAT and NET transporters leading to an increase in DA and NE levels in the synaptic cleft [153, 156, 157].”

The increase of DA promotes dopaminergic transmission by regulating (inhibiting) VMAT2, SERT (with weaker affinity), and MAOA and MAOB.

“The increase of DA promotes the dopaminergic transmission by regulating (inhibiting) other proteins: VMAT2, whose inhibition induces the DA liberation from vesicular storage and the concomitant release of cytosolic DA via DAT reverse transport [33, 187], SERT (with weaker affinity), and MAOA and MAOB [153].”