This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. Thi...

It is generally presumed that uptake transport mechanisms are of limited significance in hepatic clearance for lipophilic or high passive-permeability drugs. In this study, we evaluated the mechanistic role hepato-selective organic anion–transporting polypeptides (OATPs) 1B1/1B3 pharmacokinetics compounds representing large acid space. Intravenous 16 with molecular mass ?400–730 Da, logP ?3.5–8...

The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma co...

Hepatocyte growth factor (HGF) is known to down-regulate expression of drug-detoxifying proteins such as cytochromes P450 (P450s) in human hepatocytes. The present study was designed to determine whether HGF may also impair expression of uptake and efflux drug transporters, which constitute important determinants of the liver detoxification pathway, such as P450s. Exposure of primary human hepa...

Organic anion transporting polypeptides 1B1 and 1B3 are transporters selectively expressed on the basolateral membrane of the hepatocyte. Several studies reveal that they are involved in drug-drug interactions, cancer, and hyperbilirubinemia. In this study, we developed a set of classification models for OATP1B1 and 1B3 inhibition based on more than 1700 carefully curated compounds from literat...

The goal of this study was to determine the roles of the organic anion-transporting polypeptides (OATPs) OATP1A2, OATP1B1, and OATP1B3 and their genetic variants in the pharmacokinetics of the immunosuppressive drug mycophenolate mofetil (MMF). Using OATP-transfected human embryonic kidney (HEK) cells, we measured the uptake of mycophenolic acid (MPA) and its glucuronide (MPAG). MPAG, but not M...

Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 has been previously believed to be restricted to hepatocytes. Here we show that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 gene expression in a panel of 60 human tumor cell lin...

BACKGROUND Gene SLCO1B1, encoding solute organic anionic transport polypeptide OATP1B1, belongs to the group of candidates potentially influencing statin treatment safety. OATP1B1 regulates (not only) the hepatic uptake of statins. Its genetic variation was described as an important predictor of statin-associated myopathy in a cohort of patients treated with a maximum dose of simvastatin. Howev...