Potential role of organic anion transporting polypeptide 1B1 （OATP1B1） in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

Aim： 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 OATPIB3 mediated a higher HMME-1 uptake. OATPIB1 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. Conclusion： OATPIB1 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.