Comparative metabolism of the designer drug 4-methylthioamphetamine by hepatocytes from man, monkey, dog, rabbit, rat and mouse.
Several cases of death associated with 4-methylthioamphetamine (4-MTA) have raised public concern about the abuse of this designer drug that is usually sold as "Ecstasy" or "Flatliners". Since only very little is known about the metabolism of 4-MTA in humans we performed an in vitro study incubating racemic 4-MTA with primary hepatocytes isolated from three male human donors. Additionally, hepatocytes from male monkey (Cynomolgus), dog (Beagle), rabbit (Chinchilla), rat (Sprague-Dawley), and mouse (CD1) were examined for the metabolism of racemic 4-MTA. We observed that 4-MTA was not extensively metabolised by hepatocytes from all species examined. The main metabolite was identified as 4-methylthiobenzoic acid which, for the first time has been described as a human metabolite. In addition to metabolism we also examined 4-MTA-induced toxicity as evidenced by the ATP cellular content. Interestingly, one of the three human donors showed a dramatically increased sensitivity to the reduction in ATP content induced by 4-MTA. Comparing the species examined, the most extensive formation of 4-methylthiobenzoic acid was observed in the rabbit hepatocytes followed by human, monkey, dog and mouse hepatocytes, whereas no formation of 4-methylthiobenzoic acid was seen in the rat hepatocytes. Toxicity data suggest that rabbit hepatocytes are more resistant to 4-MTA than the other species, which may be due to the more extensive metabolism. In conclusion, we have shown that 4-methylthiobenzoic acid is the main metabolite formed from 4-MTA by human hepatocytes and also by the hepatocytes of the other tested species except the rat. Toxicity data suggest only moderate interspecies differences.
Carmo
Helena
H
REQUIMTE, Toxicology Department, Faculty of Pharmacy, Porto University, Rua Aníbal Cunha 164, 4050-047 Porto, Portugal. helenacarmo@ff.up.pt
Hengstler
Jan G
JG
de Boer
Douwe
D
Ringel
Michael
M
Carvalho
Félix
F
Fernandes
Eduarda
E
Remião
Fernando
F
dos Reys
Lesseps A
LA
Oesch
Franz
F
de Lourdes Bastos
Maria
M
D000662:Amphetamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001565:Benzoates / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008875:Middle Aged; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors
C104409:4-methylthiobenzoic acid; D000662:Amphetamines; D001565:Benzoates; D000697:Central Nervous System Stimulants; C078956:4-methylthioamphetamine