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

Abstract

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 OATP1B3 mediated a higher HMME-1 uptake. OATP1B1 exhibited a higher affinity for HMME-2 than for HMME-1 (the K m 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: 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.

Integrative Data Mining, Scaffold Analysis, and Sequential Binary Classification Models for Exploring Ligand Profiles of Hepatic Organic Anion Transporting Polypeptides

“…This scaffold has been suggested for the design of new tool compounds for therapeutic applications, mainly because of its photodynamic effects against ovarian cancer. Current findings show that porphyrin and its derivatives exert inhibitory activity against OATP1B1 . There is also evidence from activity measurements for OATP1B3, suggesting that protoporphyrin acts as a noninhibitor against OATP1B3 .…”

“…Current findings show that porphyrin and its derivatives exert inhibitory activity against OATP1B1. 44 There is also evidence from activity measurements for OATP1B3, suggesting that protoporphyrin acts as a noninhibitor against OATP1B3. 15 However, measurements for all porphyrin-associated compounds are needed to confirm the selectivity of this scaffold toward OATP1B1.…”

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

“…In vitro interaction of several porphyrins including CPs I and III with OATP1B1 has been reported (Campbell et al, 2009;Li et al, 2015). In addition, while this paper was in preparation, Bednarczyk and Boiselle (2016) assessed the in vitro transport of CP by OATP1B1 and OATP1B3 using transporter-overexpressing cells.…”

Functional characterization of putative ecdysone transporters in lepidopteran pests

“…To further characterize these transporters, rifampicin and telmisartan were tested for their efficiency to inhibit the function of lepidopteran OATP74D. Both compounds have been previously characterized to act as inhibitors of mammalian OATPs [63, 64, 65]. Although telmisartan had no impact on stable cells expressing OATP74D, rifampicin was shown to inhibit the ecdysone-induced luciferase expression when tested in cells overexpressing SfOATP74D and HaOATP74D, which is indicative that both function as typical OATPs mediating cellular uptake of 20-HE (Fig 5).…”