Cytochrome P450 2C8 and Organic Anion Transporting Polypeptide 1B1 interaction (CYP2C8/OATP1B1)

Pharmacokinetic interaction via CYP2C8/OATP1B1 describes a synergistic drug-drug interaction (DDI) mechanism involving the hepatic enzyme Cytochrome P450 2C8 (CYP2C8) and the uptake transporter Organic Anion Transporting Polypeptide 1B1 (OATP1B1) (Shitara et al., 2004). CYP2C8 is a member of the cytochrome P450 superfamily that metabolizes approximately 5% of clinically used drugs, including repaglinide, paclitaxel, and pioglitazone (Tornio et al., 2017). OATP1B1, encoded by the SLCO1B1 gene, is located on the basolateral membrane of hepatocytes and facilitates the entry of drugs from the portal blood into the liver (FDA, 2020). The interplay between these two proteins is clinically significant because certain inhibitors, such as gemfibrozil and its glucuronide metabolite, can simultaneously block both the uptake and the metabolism of a substrate (Niemi et al., 2003). This dual inhibition often results in a much larger increase in systemic drug exposure (AUC) than would be predicted by inhibiting either pathway alone, potentially leading to severe adverse effects like rhabdomyolysis or profound hypoglycemia (Shitara et al., 2004). Consequently, this interaction is a major focus of regulatory safety assessments during the drug development process.

Other names

CYP2C8-OATP1B1 interplayGemfibrozil-type interactionHepatic uptake and metabolism interplay

Simultaneous inhibition of hepatic uptake via OATP1B1 and metabolic clearance via CYP2C8, leading to synergistic increases in substrate plasma concentrations.