Stereoselectivity in the human metabolism of methamphetamine.
OBJECTIVE
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.
Li
Linghui
L
Addiction Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, San Francisco, CA 94110, USA. lilx@cpmcri.org
Everhart
Tom
T
Jacob Iii
Peyton
P
Jones
Reese
R
Mendelson
John
J
D000328:Adult; D000704:Analysis of Variance; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D004311:Double-Blind Method; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008694:Methamphetamine / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D008875:Middle Aged; D013237:Stereoisomerism; D055815:Young Adult
D000697:Central Nervous System Stimulants; D008694:Methamphetamine