Toxicokinetics of lefetamine and derived diphenylethylamine designer drugs-Contribution of human cytochrome P450 isozymes to their main phase I metabolic steps.
Lefetamine was first marketed in the 1940s as an opioid analgesic. Since withdrawal symptoms were observed during treatment, it became a controlled substance. Its N-ethyl and N-iso-propyl derivatives appeared on the illicit drug market in 2008. Metabolism studies for lefetamine and these derivatives showed that N-dealkylation was the initial step for all three substances in rats. The involvement of the ten most important human cytochrome P450 (CYP) isozymes in this N-dealkylation should be studied now. Studies showed the involvement of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 in N-dealkylation of all three compounds and additionally CYP2D6 for lefetamine and NEDPA. All kinetic profiles followed classic Michaelis-Menten kinetics. Using the relative activity factor approach, the following net clearances were calculated: for lefetamine 8% by CYP1A2, 72% by CYP2B6, 2% by CYP2C19, 1% by CYP2D6, and 17% by CYP3A4; for NEDPA 27% by CYP1A2, 30% by CYP2B6, 23% by CYP2C19, 4% by CYP2D6, and 17% by CYP3A4; for NPDPA 18% by CYP1A2, 24% by CYP2B6, 28% by CYP2C19, and 30% by CYP3A4. In addition, calculated data were compared to chemical inhibition studies in human liver microsomes. Due to the involvement of at least four enzymes in the initial metabolic steps, the risk of CYP-related drug-drug or drug-food interactions should be low.
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg (Saar), Germany.
Carina S D
CS
Wink
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg (Saar), Germany.
Golo M J
GM
Meyer
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg (Saar), Germany.
Markus R
MR
Meyer
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, D-66421 Homburg (Saar), Germany. Electronic address: hans.maurer@uks.eu.
Hans H
HH
Maurer
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015198:Designer Drugs / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007527:Isoenzymes; D008862:Microsomes, Liver; D015394:Molecular Structure; D010627:Phenethylamines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity
D015198:Designer Drugs; D007527:Isoenzymes; D010627:Phenethylamines; C011896:lephetamine; D003577:Cytochrome P-450 Enzyme System
CYP; Diphenylethylamines; Kinetic constants; LC–MS(n); Lefetamine