title: P-glycoprotein interactions of novel psychoactive substances - stimulation of ATP consumption and transport across Caco-2 monolayers.
abstract: In contrast to drugs for therapeutic use, there are only few data available concerning interactions between P-glycoprotein (P-gp) and drugs of abuse (DOA). In this work, interactions between structurally diverse DOA and P-gp were investigated using different strategies. First, the effect on the P-gp ATPase activity was studied by monitoring of ATP consumption after addition to recombinant, human P-gp. Second, DOA showing an increased ATP consumption were further characterized regarding their transport across filter grown Caco-2- monolayers. Analyses were performed by luminescence and liquid chromatography-mass spectrometry, respectively. Among the nine DOA initially screened, benzedrone, diclofensine, glaucine, JWH-200, MDBC, WIN-55,212-2 showed an increase of ATP consumption in the ATPase stimulation assay. In Caco-2 transport studies, Glaucine, JWH-200, mitragynine, WIN-55,212-2 could moreover be identified as non-transported substrates, but inhibitors of P-gp activity. Thus, drug-drug or drug-food interactions should be very likely for these compounds.
authors: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany. Electronic address: markus.meyer@uks.eu.
authors: Markus R
authors: MR
authors: Meyer
authors: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany.
authors: Lea
authors: L
authors: Wagmann
authors: Dept of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research, Saarland University, 66123 Saarbrücken, Germany.
authors: Nicole
authors: N
authors: Schneider-Daum
authors: Dept of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research, Saarland University, 66123 Saarbrücken, Germany.
authors: Brigitta
authors: B
authors: Loretz
authors: Dept of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research, Saarland University, 66123 Saarbrücken, Germany.
authors: Cristiane
authors: C
authors: de Souza Carvalho
authors: Dept of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research, Saarland University, 66123 Saarbrücken, Germany.
authors: Claus-Michael
authors: CM
authors: Lehr
authors: Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany.
authors: Hans H
authors: HH
authors: Maurer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001692:Biological Transport; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D006801:Humans; D013058:Mass Spectrometry; D011485:Protein Binding
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D000255:Adenosine Triphosphate
keywords: Drugs of abuse; Inhibitor; Novel psychoactive substances; Substrate; p-Glycoprotein