Regulation of hepatic OATP1B-type transport function by the protein kinase LYN

Src family kinases, including the Lck/Yes-related novel protein kinase (LYN), have emerged as posttranslational modulators of various transporters involved in clinically relevant pharmacokinetic drug-drug interactions. LYN expression was recently detected in hepatocytes, and we hypothesized that LYN deficiency alters the phosphorylation status and activity of transporters involved in hepatic drug disposition. An untargeted phospho-proteomic screen in livers of mice revealed that LYN deficiency was associated with significantly reduced phosphorylation of the hepatic uptake organic anion transporting polypeptide Oatp1b2 transporter that recognizes a wide range of structurally diverse xenobiotics. Using Oatp1b2 overexpressing cells and hepatocytes isolated from Lyn-deficient mice, we showed that diminished or loss of LYN expression reduced Oatp1b2-dependent cellular uptake. These outcomes could be phenocopied using the protein kinase inhibitor nilotinib. Moreover, nilotinib was found to elevate systemic exposure of the Oatp1b2 substrate, pravastatin, by approximately 2-fold in mice, which was similar to the increased pravastatin exposure seen in mice when coadministered the prototypical Oatp1b-inhibitor rifampin, but nilotinib had no effect in Oatp1b2-deficient mice. Collectively, our data indicate that LYN is a key regulator of Oatp1b2-dependent hepatic uptake and uncovers a novel potential mechanism of a drug-drug interaction that involves disrupting a regulatory kinase to transiently deactivate a rate-limiting elimination transport process of victim drugs. SIGNIFICANCE STATEMENT: This work outlines Oatp1b2 modifications in Lyn-deficient mouse livers and how loss of Lyn alters hepatic uptake and exposure of pravastatin. Such events do not occur in the absence of Oatp1b2 indicating that impaired Lyn activity promotes potentially dangerous Oatp1b-dependent drug interactions.