Adderall Metabolism
Adderall (mixed amphetamine salts) undergoes minimal hepatic metabolism, with approximately 80% of methylphenidate metabolism occurring extrahepatically, and amphetamines themselves showing negligible hepatic metabolism in vitro studies. 1
Primary Metabolic Pathways
Amphetamine and dextroamphetamine (the active components of Adderall) do not undergo substantial hepatic metabolism. Research using cryopreserved human hepatocytes and human liver microsomes demonstrated that amphetamine (AMPH) and dextroamphetamine (dAMPH) did not deplete substantially in either system, indicating these compounds may not undergo considerable hepatic metabolism 1
The major circulating metabolites of amphetamines are benzoic acid and hippuric acid, which are not produced through hepatic cytochrome P450 pathways. These metabolites were not observed in hepatocyte or microsomal systems, suggesting alternative metabolic routes 1
CYP2D6 plays only a very minimal role in amphetamine metabolism. Inhibition experiments with enzyme-specific chemical inhibitors showed negligible involvement of this polymorphic enzyme 1
Excretion Profile
Amphetamines are primarily excreted unchanged in the urine. Following a 20 mg dose of Adderall, peak amphetamine concentrations ranged from 2,645 to 5,948 ng/mL in urine, with detectable levels (≥500 ng/mL) present up to 47.5 hours post-dose 2
Adderall contains a 3:1 mixture of d- and l-enantiomers of amphetamine salts. The d-enantiomer predominates initially, with the proportion of l-enantiomer increasing over time as the enantiomers are metabolized at different rates 2
Urinary pH significantly affects amphetamine excretion. Drug concentration profiles show considerable variability due to dilution and pH fluctuations in urine samples 2
Clinical Implications for Hepatic Impairment
Dose adjustments are generally not required in patients with hepatic impairment because amphetamines are not primarily metabolized by the liver, unlike drugs with high hepatic extraction ratios (diltiazem, metoprolol, propranolol, verapamil) that require dose modifications with decreased hepatic blood flow 3
Hepatic blood flow changes with aging or liver disease have minimal impact on amphetamine clearance since the drug does not depend on hepatic metabolism for elimination 3
Important Caveats
While amphetamines themselves are not hepatically metabolized, some amphetamine analogs with methylenedioxy groups do interact with CYP2D6. For example, MDMA and related designer drugs undergo polymorphic oxidation via CYP2D6, but this does not apply to the standard amphetamine salts in Adderall 4
Lisdexamfetamine (Vyvanse), a prodrug that converts to dextroamphetamine, follows the same metabolic profile once converted and does not require hepatic dose adjustments 3