Efflux transport of nicotine, cotinine and trans-3'-hydroxycotinine glucuronides by human hepatic transporters

Autor: Erkka Järvinen, Noora Sjöstedt, Moshe Finel, Jan B. Koenderink, Heidi Kidron
Přispěvatelé: Pharmaceutical Design and Discovery group, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Division of Pharmaceutical Biosciences, Drug Delivery Unit, Moshe Finel / Principal Investigator
Rok vydání: 2019
Předmět:
Nicotine
ATP Binding Cassette Transporter
Subfamily B
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
ABCC3
METABOLISM
Pharmacology
Toxicology
030226 pharmacology & pharmacy
MULTIDRUG-RESISTANCE PROTEINS
03 medical and health sciences
chemistry.chemical_compound
Glucuronides
0302 clinical medicine
Multidrug Resistance Protein 1
medicine
ATP Binding Cassette Transporter
Subfamily G
Member 2
Humans
ASSAY
Cotinine
DISPOSITION
efflux transporters
Multidrug resistance-associated protein 2
Alkaloid
MRP3
Biological Transport
Transporter
General Medicine
UGT2B17
MEMBRANE TRANSPORTER
Multidrug Resistance-Associated Protein 2
Neoplasm Proteins
3. Good health
DRUG DISCOVERY
Liver
chemistry
317 Pharmacy
Hepatocytes
ATP-Binding Cassette Transporters
Efflux
Multidrug Resistance-Associated Proteins
Glucuronide
030217 neurology & neurosurgery
medicine.drug
Zdroj: Basic & Clinical Pharmacology & Toxicology, 125, 6, pp. 490-498
Basic & Clinical Pharmacology & Toxicology, 125, 490-498
ISSN: 1742-7835
Popis: Contains fulltext : 215788.pdf (Publisher’s version ) (Closed access) Nicotine is the addiction causing alkaloid in tobacco, and it is used in smoking cessation therapies. Although the metabolic pathways of nicotine are well known and mainly occur in the liver, the transport of nicotine and its metabolites is poorly characterized. The highly hydrophilic nature and urinary excretion of nicotine glucuronide metabolites indicate that hepatic basolateral efflux transporters mediate their excretion. We aimed here to find the transporters responsible for the hepatic excretion of nicotine, cotinine and trans-3'-hydroxycotinine (OH-cotinine) glucuronides. To this end, we tested their transport by multidrug resistance-associated proteins 1 (MRP1, ABCC1) and MRP3-6 (ABCC3-6), which are located on the basolateral membranes of hepatocytes, as well as MRP2 (ABCC2), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein 1 (MDR1, P-gp, ABCB1) that are expressed in the apical membranes of these cells. ATP-dependent transport of these glucuronides was evaluated in inside-out membrane vesicles expressing the transporter of interest. In addition, potential interactions of both the glucuronides and parent compounds with selected transporters were tested by inhibition assays. Considerable ATP-dependent transport was observed only for OH-cotinine glucuronide by MRP3. The kinetics of this transport activity was characterized, resulting in an estimated Km value of 895 micromol/L. No significant transport was found for nicotine or cotinine glucuronides by any of the tested transporters at either 5 or 50 micromol/L substrate concentration. Furthermore, neither nicotine, cotinine nor OH-cotinine inhibited MRP2-4, BCRP or MDR1. In this study, we directly examined, for the first time, efflux transport of the three hydrophilic nicotine glucuronide metabolites by the major human hepatic efflux transporters. Despite multiple transporters studied here, our results indicate that an unknown transporter may be responsible for the hepatic excretion of nicotine and cotinine glucuronides.
Databáze: OpenAIRE
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