title: Inter-Subject Variability in OCT1 Activity in 27 Batches of Cryopreserved Human Hepatocytes and Association with OCT1 mRNA Expression and Genotype.
abstract: OCT1/3 (Organic Cation Transporter-1 and -3; SLC22A1/3) are transmembrane proteins localized at the basolateral membrane of hepatocytes. They mediate the uptake of cationic endogenous compounds and/or xenobiotics. The present study was set up to verify whether the previously observed variability in OCT activity in hepatocytes may be explained by inter-individual differences in OCT1/3 mRNA levels or OCT1 genotype.
  
  
  
  Twenty-seven batches of cryopreserved human hepatocytes (male and female, age 24-88 y) were characterized for OCT activity, normalized OCT1/3 mRNA expression, and OCT1 genetic mutation. ASP+(4-[4-(dimethylamino)styryl]-N-methylpyridinium iodide) was used as probe substrate.
  
  
  
  ASP+uptake ranged between 75 ± 61 and 2531 ± 202 pmol/(min × million cells). The relative OCT1 and OCT3 mRNA expression ranged between 0.007-0.46 and 0.0002-0.005, respectively. The presence of one or two nonfunctional SLC22A1 alleles was observed in 13 batches and these exhibited significant (p = 0.04) association with OCT1 and OCT3 mRNA expression. However, direct association between genotype and OCT activity could not be established.
  
  
  
  mRNA levels and genotype of OCT only partially explain inter-individual variability in OCT-mediated transport. Our findings illustrate the necessity of in vitro transporter activity profiling for better understanding of inter-individual drug disposition behavior.
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Campus Gasthuisberg O&N II Herestraat 49 Box 921, 3000, Leuven, Belgium.
authors.forename: Sarinj
authors.initials: S
authors.lastname: Fattah
authors.affiliation: Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Abhijit Babaji
authors.initials: AB
authors.lastname: Shinde
authors.affiliation: Department Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, Netherlands.|Intensive Care and Department of Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Maja
authors.initials: M
authors.lastname: Matic
authors.affiliation: Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.affiliation: Department Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Ron H N
authors.initials: RHN
authors.lastname: van Schaik
authors.affiliation: Intensive Care and Department of Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.affiliation: KaLy-Cell, Plobsheim, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Parmentier
authors.affiliation: KaLy-Cell, Plobsheim, France.|Université de Franche-Comté, 4267, Besançon, EA, France.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Campus Gasthuisberg O&N II Herestraat 49 Box 921, 3000, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Campus Gasthuisberg O&N II Herestraat 49 Box 921, 3000, Leuven, Belgium. pieter.annaert@kuleuven.be.
authors.forename: Pieter
authors.identifier: 0000-0003-3525-7351
authors.initials: P
authors.lastname: Annaert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D015870:Gene Expression; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D061848:Optical Imaging / Q000379:methods; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D055815:Young Adult; D000099254:Organic Cation Transporter 3
chemical_list: D005456:Fluorescent Dyes; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D000099254:Organic Cation Transporter 3; C014677:1-methylpyridinium
keywords: Organic Cation Transporter (OCT); drug uptake transporters; fluorescent probe substrate; human hepatocytes; mRNA expression and genetic polymorphism