Abstract
Transporter-mediated drug–drug interactions (DDI) may induce adverse clinical events. As drugs of abuse (DOA) are marketed without preclinical safety studies, only very limited information about interplay with membrane transporters are available. Therefore, 13 DOA of various classes were tested for their in vitro affinity to the human breast cancer resistance protein (hBCRP), an important efflux transporter. As adenosine 5′-triphosphate (ATP) hydrolysis is crucial for hBCRP activity, adenosine 5′-diphosphate (ADP) formation was measured and used as in vitro marker for hBCRP ATPase activity. ADP quantification was performed by hydrophilic interaction liquid chromatography coupled to high-resolution tandem mass spectrometry and its amount in test compound incubations was compared to that in reference incubations using the hBCRP substrate sulfasalazine or the hBCRP inhibitor orthovanadate. If DOA caused stimulation or inhibition, further investigations such as Michaelis–Menten kinetic modeling or IC50 value determination were conducted. Among the tested DOA, seven compounds showed statistically significant hBCRP ATPase stimulation. The entactogen 3,4-BDB and the plant alkaloid mitragynine were identified as strongest stimulators. Their affinity to the hBCRP ATPase was lower than that of sulfasalazine but comparable to that of rosuvastatin, another hBCRP model substrate. Five DOA showed statistically significant hBCRP ATPase inhibition. Determination of IC50 values identified the synthetic cannabinoid receptor agonists JWH-200 and WIN 55,212-2 as the strongest inhibitors comparable to orthovanadate. The present study clearly demonstrated that tested DOA show in part high affinities to the hBCRP within the range of model substrates or inhibitors. Thus, there is a risk of hBCRP-mediated DDI, which needs to be considered in clinical settings.
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References
Brandt SD, Tirunarayanapuram SS, Freeman S et al (2008) Microwave-accelerated synthesis of psychoactive deuterated N,N-dialkylated-[α,α,β,β-d4]-tryptamines. J Label Compd Radiopharm 51(14):423–429
Carter N, Rutty GN, Milroy CM, Forrest AR (2000) Deaths associated with MBDB misuse. Int J Leg Med 113(3):168–170
Chauret N, Gauthier A, Nicoll-Griffith DA (1998) Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes. Drug Metab Dispos 26(1):1–4
Dinger J, Meyer MR, Maurer HH (2016) In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach. Arch Toxicol 90(2):305–318
EMA (2012) Guideline on the investigation of drug interactions, vol CPMP/EWP/560/95/Rev. 1 Corr. 2**, 2012 edn. European Medicines Agency, London. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed 21 May 2018
Endres CJ, Hsiao P, Chung FS, Unadkat JD (2006) The role of transporters in drug interactions. Eur J Pharm Sci 27(5):501–517
FDA (2017) In vitro metabolism- and transporter-mediated drug–drug interaction studies, guidance for industry. FDA (Food and Drug Administration). https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf. Accessed 21 May 2018
Gupta A, Zhang Y, Unadkat JD, Mao Q (2004) HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther 310(1):334–341
Helfer AG, Michely JA, Weber AA, Meyer MR, Maurer HH (2015) Orbitrap technology for comprehensive metabolite-based liquid chromatographic–high resolution-tandem mass spectrometric urine drug screening—exemplified for cardiovascular drugs. Anal Chim Acta 891:221–233
Hira D, Terada T (2018) BCRP/ABCG2 and high-alert medications: biochemical, pharmacokinetic, pharmacogenetic, and clinical implications. Biochem Pharmacol 147:201–210
Holland ML, Lau DT, Allen JD, Arnold JC (2007) The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. Br J Pharmacol 152(5):815–824
Huang L, Wang Y, Grimm S (2006) ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos 34(5):738–742
International Transporter C, Giacomini KM, Huang SM et al (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236
Ishikawa T, Kasamatsu S, Hagiwara Y, Mitomo H, Kato R, Sumino Y (2003) Expression and functional characterization of human ABC transporter ABCG2 variants in insect cells. Drug Metab Pharmacokinet 18(3):194–202
Jani M, Szabo P, Kis E, Molnar E, Glavinas H, Krajcsi P (2009) Kinetic characterization of sulfasalazine transport by human ATP-binding cassette G2. Biol Pharm Bull 32(3):497–499
Karinen R, Tuv SS, Oiestad EL, Vindenes V (2015) Concentrations of APINACA, 5F-APINACA, UR-144 and its degradant product in blood samples from six impaired drivers compared to previous reported concentrations of other synthetic cannabinoids. Forensic Sci Int 246:98–103
Kaskova ZM, Tsarkova AS, Yampolsky IV (2016) 1001 lights: luciferins, luciferases, their mechanisms of action and applications in chemical analysis, biology and medicine. Chem Soc Rev 45(21):6048–6077
Kruijtzer CM, Beijnen JH, Rosing H et al (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20(13):2943–2950
Mao Q, Lai Y, Wang J (2018) Drug Transporters in xenobiotic disposition and pharmacokinetic prediction. Drug Metab Dispos 46(5):561–566
Meyer MR, Orschiedt T, Maurer HH (2013) Michaelis–Menten kinetic analysis of drugs of abuse to estimate their affinity to human P-glycoprotein. Toxicol Lett 217(2):137–142
Meyer MR, Wagmann L, Schneider-Daum N et al (2015) P-glycoprotein interactions of novel psychoactive substances—stimulation of ATP consumption and transport across Caco-2 monolayers. Biochem Pharmacol 94(3):220–226
Muller F, Fromm MF (2011) Transporter-mediated drug–drug interactions. Pharmacogenomics 12(7):1017–1037
Philipp AA, Wissenbach DK, Zoerntlein SW, Klein ON, Kanogsunthornrat J, Maurer HH (2009) Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometry. J Mass Spectrom 44(8):1249–1261
Sarkadi B, Homolya L, Szakacs G, Varadi A (2006) Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev 86(4):1179–1236
Staeheli SN, Gascho D, Ebert LC, Kraemer T, Steuer AE (2017) Time-dependent postmortem redistribution of morphine and its metabolites in blood and alternative matrices-application of CT-guided biopsy sampling. Int J Leg Med 131(2):379–389
Strojny N, de Silva JA (1985) Determination of diclofensine, an antidepressant agent, and its major metabolites in human plasma by high-performance liquid chromatography with fluorometric detection. J Chromatogr 341(2):313–331
Toennes SW, Geraths A, Pogoda W et al (2017) Pharmacokinetic properties of the synthetic cannabinoid JWH-018 and of its metabolites in serum after inhalation. J Pharm Biomed Anal 140:215–222
Tournier N, Chevillard L, Megarbane B, Pirnay S, Scherrmann JM, Decleves X (2010) Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol 13(7):905–915
Trakulsrichai S, Sathirakul K, Auparakkitanon S et al (2015) Pharmacokinetics of mitragynine in man. Drug Des Dev Ther 9:2421–2429
UNODC (2017) World drug report. United Nations publication. https://www.unodc.org/wdr2017/index.html. Accessed 21 May 2018
Upreti GC (1984) Colorimetric estimation of inorganic phosphate in colored and/or turbid biological samples: assay of phosphohydrolases. Anal Biochem 137(2):485–492
Wagmann L, Brandt SD, Kavanagh PV, Maurer HH, Meyer MR (2017a) In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks. Toxicol Lett 272:84–93
Wagmann L, Maurer HH, Meyer MR (2017b) An easy and fast adenosine 5′-diphosphate quantification procedure based on hydrophilic interaction liquid chromatography–high resolution tandem mass spectrometry for determination of the in vitro adenosine 5′-triphosphatase activity of the human breast cancer resistance protein ABCG2. J Chromatogr A 1521:123–130
Wang X, Zhang ZY, Arora S et al (2018) Effects of rolapitant administered intravenously or orally on the pharmacokinetics of digoxin (P-glycoprotein substrate) and sulfasalazine (breast cancer resistance protein substrate) in healthy volunteers. J Clin Pharmacol 58(2):202–211
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The authors like to thank Achim T. Caspar, Lilian H. J. Richter, Gabriele Ulrich, and Armin A. Weber for their support.
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Wagmann, L., Maurer, H.H. & Meyer, M.R. Inhibition and stimulation of the human breast cancer resistance protein as in vitro predictor of drug–drug interactions of drugs of abuse. Arch Toxicol 92, 2875–2884 (2018). https://doi.org/10.1007/s00204-018-2276-y
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DOI: https://doi.org/10.1007/s00204-018-2276-y