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Transport of coproporphyrins I and III by organic anion transporting polypeptides (OATP) 1B1 and 1B3

Bednarczyk, Dallas and Boiselle, Carri (2015) Transport of coproporphyrins I and III by organic anion transporting polypeptides (OATP) 1B1 and 1B3. Xenobiotica, 46 (5). pp. 457-466. ISSN 1366-5928


To better assess drug interaction risk and safety issues, as well as reduce drug development costs and late stage failure within the pharmaceutical industry, the identification of novel biomarkers of transport is desirable. Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are polyspecific transporters that mediate the transport of endogenous compounds and xenobiotics into hepatocytes. Inactivating mutations of both OATP1B1 and OATP1B3 alleles lead to Rotor syndrome, a disease characterized by coproporphyrinuria, an elevated urinary excretion of coproporphyrins I and III. It was hypothesized that the transport of coproporphyrins I and III was mediated by OATP1B1 and OATP1B3. This hypothesis was supported by the current study using CHO cells transfected by OATP1B1 and HEK cells transfected by OATP1B3. The transport of each coproporphyrin by OATP1B1 and OATP1B3 was time-dependent and could be saturated. OATP1B1 mediated high affinity transport of coproporphyrins I and III (Km = 0.49 and 0.64 µM, respectively), as did OATP1B3 (Km = 0.86 and 0.96 µM, respectively). The OATP1B-mediated transport of each coproporphyrin was inhibited by rifamycin SV and atazanavir, with rifamycin SV demonstrating sub-micromolar inhibitor potency towards both transporters using either coproporphyrin as the in vitro probe substrate. The inhibitory potency of atazanavir was 5-10-fold less than that of rifamycin SV. The identification of coproporphyrins I and III as OATP1B substrates may have utility in the in vivo assessment of function and interaction with OATP1B1 and OATP1B3. As biomarkers, the coproporphyrins may enable the early in vivo assessment of OATP1B function and help identify drug interactions.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45


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