Intracellular drug exposure is influenced by cell- and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (Fic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Fic is affected by cellular drug disposition processes. We first investigated the impact of...

Several members of the organic anion transporting polypeptide (OATP/Oatp) family of uptake transporters are expressed in the hepatocyte sinusoidal membrane in humans and preclinical species. The mouse liver specific Oatp is Oatp1b2, and the human homologs most closely related are OATP1B1 and 1B3. The substrate specificity of these transporters is broad, and the widely accepted view is that they...

The organic anion transporting polypeptides OATPs are key membrane transporters for which crystal structures are not currently available. They transport a diverse array of xenobiotics and are expressed at the interface of hepatocytes, renal tubular cells, enterocytes, and the choroid plexus. To aid the understanding of the key molecular features for substrate-transporter interactions, pharmacop...

Hepatic uptake and biliary excretion of olmesartan, a new angiotensin II blocker, were investigated in vitro using human hepatocytes, cells expressing uptake transporters and canalicular membrane vesicles, and in vivo using Eisai hyperbilirubinemic rats (EHBR), inherited multidrug resistance-associated protein (mrp2)-deficient rats. The uptake by human hepatocytes reached saturation with a Mich...

There has been remarkable progress during the past decade in understanding of how genetic variations in drug metabolizing enzymes and transporters contribute to observed variation in drug responsiveness. Among drug transporters, the organic anion transporting polypeptide (OATP) class of transporters have proven to be remarkably important to the cellular uptake disposition of a variety of clinic...

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by ...

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...

The objective of this study was to clarify the mechanism underlying hepatic uptake of dioscin (diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside), an herbal ingredient with antihepatitis activity, in rats and humans. The liver uptake index (LUI) in vivo, perfused rat liver in situ, rat liver slices, isolated rat hepatocytes, and human organic anion-transporting polypeptide (OATP)-trans...

We studied the precision of quantification of organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP2B1, and P-glycoprotein (P-gp) in human livers by surrogate peptide based LC-MS/MS approach using two different internal standards: stable isotope labeled peptide (SIL) versus stable isotope labeled protein (SILAC). The SIL peptides were procured commercially and the SILAC proteins w...