can enter monoamine neurons; this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft. lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. the attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. a relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine. as opposed to adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamine salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula. studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are fda-approved for treatment of adhd, but still has a high abuse potential when this dosage is exceeded by over 100%. pharmacokinetics dextroamphetamine concentrations after oral administration of a single equimolar dose of dextroamphetamine sulfate immediate-release (ir) (40 mg; equivalent to 30 mg dextroamphetamine free-base) and lisdexamfetamine dimesylate (100 mg) in healthy adults. cmax, t1/2, and auc∞ were all similar between the two drugs, while tlag (1.5 hours vs. 0.8 hours) and tmax (4.6 hours vs. 3.3 hours) were longer for lisdexamfetamine than with dextroamphetamine. the oral bioavailability of amphetamine varies with gastrointestinal ph; it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine. amphetamine is a weak base with a pka of 9.9; consequently, when the ph is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. conversely, an acidic ph means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins. following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue. the half-lives of amphetamine enantiomers differ and vary with urine ph. at normal urine ph, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. highly acidic urine will reduce the enantiomer half-lives to 7 hours; highly alkaline urine will increase the half-lives up to 34 hours. the immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary ph. when the urinary ph is basic, amphetamine is in its free base form, so less is excreted. when urine ph is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. following oral administration, amphetamine appears in urine within 3 hours. roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose. lisdexamfetamine is a prodrug of dextroamphetamine. it is not as sensitive to ph as amphetamine when being absorbed in the gastrointestinal tract. following absorption into the blood stream, lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acid l-lysine by hydrolysis via undetermined aminopeptidase enzymes. this is the rate-limiting step in the bioactivation of lisdexamfetamine. the elimination half-life of lisdexamfetamine is generally less than 1 hour. due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine. presumably due to its rate-limited activation by red blood cells, intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine. the pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously. hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of lisdexamfetamine. because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential. cyp2d6, dopamine β-hydroxylase (dbh), flavin-containing monooxygenase 3 (fmo3), butyrate-coa ligase (xm-ligase), and glycine n-acyltransferase (glyat) are the enzymes known to metabolize amphetamine or its metabolites in humans. amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine, and norephedrine. the main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, n-oxidation, n-dealkylation, and deamination. the known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following: metabolic pathways of amphetamine in humans 4-hydroxyphenylacetone phenylacetone benzoic acid hippuric acid amphetamine norephedrine 4-hydroxyamphetamine 4-hydroxynorephedrine para-hydroxylation para-hydroxylation para-hydroxylation cyp2d6 cyp2d6 unidentified beta-hydroxylation beta-hydroxylation dbh dbh oxidativedeamination fmo3 oxidation unidentified glycineconjugation xm-ligaseglyat the primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine; at normal urine ph, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row). the remaining 10–20% is excreted as the active metabolites. benzoic acid is metabolized by xm-ligase into an intermediate product, benzoyl-coa, which is then metabolized by glyat into hippuric acid. chemistry lisdexamfetamine is a substituted amphetamine with an amide linkage formed by the condensation of dextroamphetamine with the carboxylate group of the essential amino acid l-lysine. the reaction occurs with retention of stereochemistry, so the product lisdexamfetamine exists as a single stereoisomer. there are many possible names for lisdexamfetamine based on iupac nomenclature, but it is usually named as n--l-lysinamide or (2s)-2,6-diamino-n-hexanamide. the condensation reaction occurs with loss of water: (s)-phch2ch(ch3)nh2 + (s)-hoocch(nh2)ch2ch2ch2ch2nh2 → (s,s)-phch2ch(ch3)nhc(o)ch(nh2)ch2ch2ch2ch2nh2 + h2o amine functional groups are vulnerable to oxidation in air and so pharmaceuticals containing them are usually formulated as salts where this moiety has been protonated. this increases stability, water solubility, and, by converting a molecular compound to an ionic compound, increases the melting point and thereby ensures a solid product. in the case of lisdexamfetamine, this is achieved by reacting with two equivalents of methanesulfonic acid to produce the dimesylate salt, a water-soluble (792 mg ml−1) powder with a white to off-white color. phch2ch(ch3)nhc(o)ch(nh2)ch2ch2ch2ch2nh2 + 2 ch3so3h → 2 comparison to other formulations lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. the following table compares the drug to other amphetamine pharmaceuticals. amphetamine base in marketed amphetamine medications drug formula molar mass amphetamine base amphetamine basein equal doses doses withequal basecontent (g/mol) (percent) (30 mg dose) total base total dextro- levo- dextro- levo- dextroamphetamine sulfate (c9h13n)2•h2so4 368.49 270.41 73.38% 73.38% — 22.0 mg — 30.0 mg amphetamine sulfate (c9h13n)2•h2so4 368.49 270.41 73.38% 36.69% 36.69% 11.0 mg 11.0 mg 30.0 mg adderall 62.57% 47.49% 15.08% 14.2 mg 4.5 mg 35.2 mg 25% dextroamphetamine sulfate (c9h13n)2•h2so4 368.49 270.41 73.38% 73.38% — 25% amphetamine sulfate (c9h13n)2•h2so4 368.49 270.41 73.38% 36.69% 36.69% 25% dextroamphetamine saccharate (c9h13n)2•c6h10o8 480.55 270.41 56.27% 56.27% — 25% amphetamine aspartate monohydrate (c9h13n)•c4h7no4•h2o 286.32 135.21 47.22% 23.61% 23.61% lisdexamfetamine dimesylate c15h25n3o•(ch4o3s)2 455.49 135.21 29.68% 29.68% — 8.9 mg — 74.2 mg amphetamine base suspension c9h13n 135.21 135.21 100% 76.19% 23.81% 22.9 mg 7.1 mg 22.0 mg history