Summary of tools that could be available to assess the induction of human OATPs
| Approach | Comment | References (Where Available) |
|---|---|---|
| 1. In vitro nuclear hormone receptor transactivation assays (assumes that receptor agonism drives OATP induction) | Important to assess if compound is PXR, CAR, LXR, FXR, or vitamin D receptor agonist | Meyer Zu Schwabedissen et al., 2010; Howe et al., 2011; Eloranta et al., 2012 |
| 2. Primary human cells in vitro (plated hepatocytes, tissue slices); OATP protein and mRNA expression assessment vs. CYP and ABC transporter expression | Reports available describing assessment of OATP induction vs. CYP and ABC transporters | Described in Tables 4 and 5 |
| 3. Primary human cells in vitro (three-dimensional organoids, tissue-on-a-chip); OATP protein and mRNA expression assessment vs. CYP and ABC transporter expression | Needs validation for OATP induction | To date, no references describing OATP induction in organoids or tissue-on-a-chip |
| 4. Humanized rodents (e.g., humanized OATP, humanized liver); OATP protein and mRNA tissue expression assessment vs. CYP and ABC transporter expression | Needs validation for various PXR, CAR, FXR, and LXR agonists | To date, no references describing OATP induction in the tissues of humanized rodents |
| 5. Nonhuman primate (primary hepatocytes) | Report available for PXR agonist (RIF) describing assessment of cynomolgus monkey OATP induction vs. CYP and ABC transporters | Niu et al., 2019 |
| 6. Nonhuman primate tissue biopsy (e.g., gut and liver) following administration of inducer for greater than 7 days | Targeted and nontargeted transcriptomic and proteome analysis; compare OATP vs. CYP3A and ABC transporters | To date, no references describing OATP tissue expression profiling following inducer |
| 7. Tissue biopsy (intestine and/or liver) of human subjects following administration of inducer | Reports available describing assessment of OATP induction vs. CYP3A and ABC transporters | Described in Table 3 |
| 8. Support of clinical induction study using a liquid biopsy approach (plasma-derived tissue exosomes or circulating human lymphocytes) | One report describing the use of circulating human lymphocytes, but liquid biopsy approaches need validation | Yang et al., 2019 |
| 9. Use of a selective OATP biomarker or probe drug that is minimally influenced by CYP and/or ABC transporter induction (e.g., gut and/or liver MRP2, Pgp, or BCRP) | Selective gut and/or liver OATP probe has not been identified, characterized, and validated; CPI might be an option, provided test compound does not inhibit OATP and present autoinduction like RIF | To date, there are no references describing selective OATP biomarkers or drug probes suitable for multidose OATP induction studies |