Publications

• Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: <i>In Vitro</i> Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates.

  Medwid S., Price H.R., Taylor D.P., Mailloux J., Schwarz U.I., Kim R.B., Tirona R.G.

  Organic anion transporting polypeptide 2B1 (OATP2B1, gene <i>SLCO2B1</i>) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of <i>SLCO2B1</i> genetic variation on pharmacokinetics is poor ... >> More

  Organic anion transporting polypeptide 2B1 (OATP2B1, gene <i>SLCO2B1</i>) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of <i>SLCO2B1</i> genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) <i>in vitro</i>. Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with <i>SLCO2B1</i> genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the <i>SLCO2B1</i> c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while <i>SLCO2B1</i> c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and <i>SLCO1B1</i> genotypes. No association was observed between <i>SLCO2B1</i> variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with <i>SLCO2B1</i> c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities <i>in vitro</i> were not fully aligned with their associations to plasma concentrations of endogenous substrates <i>in vivo</i>. Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity. << Less

  Front Pharmacol 12:713567-713567(2021) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Organic anion transporting polypeptide (OATP)-mediated transport of coproporphyrins I and III.

  Bednarczyk D., Boiselle C.

  1. Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are polyspecific transporters that mediate the transport of organic acids into hepatocytes. Inactivating mutations of both OATP1B1 and OATP1B3 alleles lead to Rotor syndrome, a disease characterized by coproporphyrinuria, an elevated u ... >> More

  1. Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are polyspecific transporters that mediate the transport of organic acids 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 transport of coproporphyrins I and III was mediated by OATP1B1 and OATP1B3. 2. This hypothesis was tested using cells transfected with OATP1B1 and OATP1B3. OATP1B-mediated transport of coproporphyrin was time-dependent and concentration-dependent. OATP1B1-mediated transport of coproporphyrins I and III (Km = 0.13 and 0.22 µM, respectively), as did OATP1B3 (Km = 3.25 and 4.61 µM, respectively). The OATP1B-mediated transport of each coproporphyrin was inhibited by rifampicin. 3. The specificity of coproporphyrin transport was also investigated where OATP2B1 demonstrated meaningful transport of coproporphyrin III (Km = 0.31 µM), while OCT1, OCT2, OAT1, OAT3 and NTCP were negative for coproporphyrin transport. 4. The identification of coproporphyrins as OATP substrates in vitro more clearly defines the role of OATPs in the hepatic disposition and renal excretion of coproporphyrins I and III and provides compelling evidence for future in vivo exploration of coproporphyrins as biomarkers of OATP activity. << Less

  Xenobiotica 46:457-466(2016) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.