Interaction between HIV Protease Inhibitors (PIs) and Hepatic Transporters in Sandwich Cultured Human Hepatocytes: Implication for PI-based DDIs

摘要

Although HIV protease inhibitors (PIs) produce profound metabolic interactions through inactivation/inhibition of CYP3A enzymes, their role as victims of transporter-based drug-drug interactions (DDIs) is less well understood. Therefore, we investigated if the PIs, nelfinavir (NFV), ritonavir (RTV), lopinavir (LPV), or amprenavir (APV) were transported into sandwich-cultured human hepatocytes (SCHH), and whether OATPs contributed to this transport. Our findings showed that except for ³H-APV, no significant decrease in the total hepatocyte accumulation of the ³H-PIs was detected in the presence of the corresponding unlabeled PI, indicating that the uptake of the other PIs was not mediated. Further, hepatocyte biliary efflux studies using ³H-APV and unlabeled APV confirmed this decrease to be due to inhibition of sinusoidal influx transporter(s) and not the canalicular efflux transporters. Moreover, this sinusoidal transport of APV was not OATP-mediated. Our results indicate the hepatic uptake of NFV, RTV, or LPV was primarily mediated by passive diffusion. APV’s hepatic uptake was mediated by an unidentified sinusoidal transporter(s). Therefore, NFV, RTV or LPV will not be victims of DDIs involving inhibition of hepatic influx transporters; however, the disposition of APV may be affected if its sinusoidal transport is inhibited.