title: Interactions between 3,4-methylenedioxymethamphetamine, methamphetamine, ketamine, and caffeine in human intestinal Caco-2 cells and in oral administration to rats.
abstract: Amphetamine-type stimulants (ATSs) are often abused orally in the form of tablets for recreational purposes. The ATS tablets contain one or more active ingredients such as 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (MA), ketamine (KA), and caffeine (CF). The aim of this work is to determine whether such components in tablets interact with each other in intestinal absorption. The interactions between MDMA, MA, KA, and CF in the uptake and permeation by human intestinal epithelial Caco-2 cell line were investigated in monolayer cultures. MDMA, MA, and KA mutually inhibited the uptakes by Caco-2 cells. The inhibition of MA uptake by KA was the greatest of all combinations (72.6% inhibition). Similarly, MDMA, MA, and KA mutually inhibited the permeation from the apical to the basolateral side through Caco-2 cells. Although CF did not affect the uptakes of MDMA, MA, and KA, CF enhanced the permeation of MDMA in comparison to MDMA alone. In addition, the interaction of MA with KA and that of MDMA with CF in intestinal absorption were investigated by oral administration to rats. The area under the plasma concentration-time curve of MA significantly decreased by co-administration with KA in comparison to MA alone, while that of MDMA significantly increased by co-administration with CF in comparison to MDMA alone. The results in rats were similar to those in Caco-2 cells. These findings suggest that the intestinal absorption of similar compounds with amine moieties such as MDMA, MA, and KA are mediated by a common transport system, and that CF affects the absorption of MDMA in a different way from the transport system. In human, intakes of ATS tablets mixed with such components might result in similar interactions in intestinal absorption to those in Caco-2 cells and rats.
authors.affiliation: National Research Institute of Police Science, Kashiwanoha, Kashiwa, Chiba, Japan. kuwayama@nrips.go.jp <kuwayama@nrips.go.jp>
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Kanamori
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsujikawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Miyaguchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwata
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Kamo
authors.forename: Tohru
authors.initials: T
authors.lastname: Kishi
mesh_terms: D000284:Administration, Oral; D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells / Q000378:metabolism*; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D053593:Forensic Toxicology; D006213:Hallucinogens / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007649:Ketamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000778:Anesthetics, Dissociative; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D002110:Caffeine; D008694:Methamphetamine; D007649:Ketamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine