Oxidation of 5-methoxy-N,N-diisopropyltryptamine in rat liver microsomes and recombinant cytochrome P450 enzymes.
The oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), a tryptamine-type designer drug, was studied using rat liver microsomal fractions and recombinant cytochrome P450 (CYP) enzymes. 5-MeO-DIPT was biotransformed mainly into a side-chain N-deisopropylated metabolite and partially into an aromatic ring O-demethylated metabolite in liver microsomal fractions from untreated rats of both sexes. This metabolic profile is different from our previous findings in human liver microsomal fractions, in which the aromatic ring O-demethylation was the major pathway whereas the side-chain N-deisopropylation was minor [Narimatsu S, Yonemoto R, Saito K, Takaya K, Kumamoto T, Ishikawa T, et al. Oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes. Biochem Pharmacol 2006;71:1377-85]. Kinetic and inhibition studies indicated that the side-chain N-dealkylation is mediated by CYP2C11 and CYP3A2, whereas the aromatic ring O-demethylation is mediated by CYP2D2 and CYP2C6 in untreated male rats. Pretreatment of male rats with beta-naphthoflavone (BNF) produced an aromatic ring 6-hydroxylated metabolite. Recombinant rat and human CYP1A1 efficiently catalyzed 5-MeO-DIPT 6-hydroxylation under the conditions used. These results provide valuable information on the metabolic fate of 5-MeO-DIPT in rats that can be used in the toxicological study of this designer drug.
Narimatsu
Shizuo
S
Laboratory of Health Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama, Japan.
Yonemoto
Rei
R
Masuda
Kazufumi
K
Katsu
Takashi
T
Asanuma
Masato
M
Kamata
Tooru
T
Katagi
Munehiro
M
Tsuchihashi
Hitoshi
H
Kumamoto
Takuya
T
Ishikawa
Tsutomu
T
Naito
Shinsaku
S
Yamano
Shigeru
S
Hanioka
Nobumitsu
N
D008735:5-Methoxytryptamine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000494:pharmacology
D011994:Recombinant Proteins; C033696:5-methoxy-N,N-diisopropyltryptamine; D008735:5-Methoxytryptamine; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System