Abstract
"Ecstasy" [(±)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (±)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles *2, *10, and *17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (Vmax/Km) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (Km). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6*2, *17, and, particularly, *10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2111-2119 |
| Number of pages | 9 |
| Journal | Biochemical Pharmacology |
| Volume | 63 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 2002 |
| Externally published | Yes |
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Keywords
- (±)-3,4-Methylenedioxymethamphetamine
- Cytochrome P450 2D6
- Drug interactions
- Drug metabolism
- Pharmacogenetics
- Pharmacokinetics
ASJC Scopus subject areas
- Pharmacology
Cite this
Reduced (±)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro. / Ramamoorthy, Yamini; Yu, Aiming; Suh, Nina; Haining, Robert L.; Tyndale, Rachel F.; Sellers, Edward M.
In: Biochemical Pharmacology, Vol. 63, No. 12, 15.06.2002, p. 2111-2119.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Reduced (±)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro
AU - Ramamoorthy, Yamini
AU - Yu, Aiming
AU - Suh, Nina
AU - Haining, Robert L.
AU - Tyndale, Rachel F.
AU - Sellers, Edward M.
PY - 2002/6/15
Y1 - 2002/6/15
N2 - "Ecstasy" [(±)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (±)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles *2, *10, and *17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (Vmax/Km) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (Km). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6*2, *17, and, particularly, *10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.
AB - "Ecstasy" [(±)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (±)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles *2, *10, and *17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (Vmax/Km) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (Km). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6*2, *17, and, particularly, *10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.
KW - (±)-3,4-Methylenedioxymethamphetamine
KW - Cytochrome P450 2D6
KW - Drug interactions
KW - Drug metabolism
KW - Pharmacogenetics
KW - Pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=0037096036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037096036&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(02)01028-6
DO - 10.1016/S0006-2952(02)01028-6
M3 - Article
C2 - 12110370
AN - SCOPUS:0037096036
VL - 63
SP - 2111
EP - 2119
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 12
ER -