title: Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers.
abstract: OBJECTIVE
  Hematoporphyrin monomethyl ether (HMME), which consists of equal amounts of isomers HMME-1 and HMME-2, is a novel porphyrin-related drug for photodynamic therapy. This study was aimed to investigate the uptake transporter-mediated selective uptake of HMME into the liver and to identify the major uptake transporter isoforms involved.
  
  
  METHODS
  Adult SD rats were intravenously injected with a single dose of HMME (5 mg/kg) with or without rifampicin (an inhibitor of organic anion transporting polypeptides OATP1B1 and OATP1B3, 25 mg/kg). Blood samples were collected, and HMME concentrations were measured using LC-MS/MS. Rat hepatocytes, human hepatocytes and HEK293 cells expressing OATP1B1, OATP1B3, or OATP2B1 were used to investigate the uptake of HMME or individual isomers in vitro.
  
  
  RESULTS
  Co-administration of rifampicin significantly increased the exposure of HMME isomers, and decreased the AUC ratio of HMME-1 to HMME-2 from 1.98 to 1.56. The uptake of HMME-2 into human hepatocytes and the HEK293 cells expressing OATP1B1 or OATP2B1 in vitro was 2-7 times greater than that of HMME-1, whereas OATP1B3 mediated a higher HMME-1 uptake. OATP1B1 exhibited a higher affinity for HMME-2 than for HMME-1 (the Km values were 0.63 and 5.61 μmol/L, respectively), which were similar to those in human hepatocytes. By using telmisartan (a non-specific OATP inhibitor) and rifampicin, OATP2B1 was demonstrated to account for <20% of hepatic HMME uptake.
  
  
  CONCLUSIONS
  OATP1B1 is the major transporter involved in the rapid hepatic uptake of HMME, and the greater uptake of HMME-2 by OATP1B1 may lead to a lower exposure of HMME-2 than HMME-1 in humans.
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiu-li
authors.initials: XL
authors.lastname: Li
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zi-tao
authors.initials: ZT
authors.lastname: Guo
authors.affiliation: College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
authors.forename: Ye-dong
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiao-yan
authors.initials: XY
authors.lastname: Chen
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Da-fang
authors.initials: DF
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D057809:HEK293 Cells; D006415:Hematoporphyrins / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006415:Hematoporphyrins; D027361:Organic Anion Transporters; C494379:hematoporphyrin monomethyl ether