Stereoselectivity in the human metabolism of methamphetamine

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Methamphetamine (MA) is a chiral compound. • The S‐(+) enantiomer is more commonly abused and is more potent in producing central nervous system and cardiovascular effects than the R‐(−) enantiomer. • Studies describing the metabolism of MA have mainly been done with the S‐(+)‐isomer; pharmacokinetic data for R‐(−)‐MA or racemic MA are very limited. WHAT THIS STUDY ADDS • Stereoselectivity exists in the metabolism of MA. • Urinary excretion of para hydroxymethamphetamine (pOH‐MA) was found to be least affected by stereoselectivity. • It is suggested that pOH‐MA may be a more stable biomarker of MA abuse. AIM To characterize the formation and urinary elimination of metabolites of S‐(+) and R‐(−) methamphetamine (MA) in humans. METHODS In this 12‐subject, six‐session, double‐blind, placebo‐controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH‐MA) and amphetamine (AMP) were determined in urine after intravenous doses of S‐(+)‐MA 0.25 and 0.5 mg kg −1 , R‐(−)‐MA 0.25 and 0.5 mg kg −1 , racemic MA 0.5 mg kg −1 , or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography‐mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S‐(+)‐AMP vs. 2% to R‐(−)‐AMP ( P < 0.001). Furthermore, less R‐(−)‐pOH‐MA was excreted in the urine compared with S‐(+)‐pOH‐MA (8% vs. 11%, P = 0.02). Correspondingly, S‐(+)‐MA excretion was less than R‐(−)‐MA (42% vs. 52%; P = 0.005). CONCLUSIONS The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH‐MA (8–11%) than AMP (2–7%). The formation of pOH‐MA was less affected by the MA enantiomer administered, suggesting that urine pOH‐MA may be a more stable biomarker of MA metabolism.