Irreversible inhibition of CYP2D6 by (-)-chloroephedrine, a possible impurity in methamphetamine

(+)- and (-)-Chloroephedrine, and their respective aziridines, cis- and trans-1,2-dimethyl-3-phenylaziridine, have been reported present in clandestinely synthesized methamphetamine. Since methamphetamine and structurally related compounds are potential substrates for human liver CYP2D6, the possible interaction of the chloroephedrines with human liver CYP2D6 was evaluated. Computational methods (using Flexidock and HINT in SYBYL) were used to determine the feasibility of (+)- or (-)-chloroephedrine and cis- or trans-1,2-dimethyl-3-phenylaziridine binding in the active site of a three dimensional CYP2D6 molecular model. Although modeling indicates both (+)- and (-)-chloroephedrine would bind comparably to methamphetamine, the binding energies of cis- or trans-1,2-dimethyl-3-phenylaziridine products indicate a preference for trans-1,2-dimethyl-3-phenylaziridine, the product formed from (-)-chloroephedrine. The effects of (+)- and (-)-chloroephedrine on the metabolism of dextromethorphan in human liver microsomes were then experimentally evaluated. (+)-Chloroephedrine (50 micro M) had no effect on human CYP2D6. (-)-Chloroephedrine appeared to be selective for human CYP2D6 versus CYP1A2 and CYP3A4/5. The inhibition of CYP2D6 was time-dependent, not dependent on metabolic activation, and irreversible. It appeared to bind at the active site of CYP2D6 with an apparent K(i) of 226 micro M, with a k(int) of 0.039 min(-1), and a t(1/2) of 23 min. Due to the irreversible nature of this inhibition, this impurity in clandestinely synthesized methamphetamine may be important and warrant further study.