Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1

Abstract

Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the Slco2b1 gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wildtype (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC 0-last) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced C max by 80% and 88%, respectively, while the AUC 0-last values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine C max and AUC 0-last values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

Imaging-Based Characterization of a Slco2b1(-/-) Mouse Model Using [11C]Erlotinib and [99mTc]Mebrofenin as Probe Substrates

“…A step forward in efforts to better understand the intrinsic role of OATP2B1 in drug disposition has been the recent generation of Slco2b1 (-/-) mice [ 12 , 13 ]. A first characterization of these novel mouse models revealed significantly lower plasma concentrations of orally administered fexofenadine and fluvastatin in Slco2b1 (-/-) mice as compared with wild-type mice, which supported a role of OATP2B1 in the intestinal absorption of these drugs [ 12 , 13 ]. In an attempt to address the role of hepatic OATP2B1, the plasma pharmacokinetics (PK) of fluvastatin were also studied after intravenous (i.v.)…”

Pharmacogenomics in the era of next generation sequencing – from byte to bedside

“…In recent years, CRISPR/Cas9 has also been used to genetically engineer cell lines to express pharmacogenetic variants for functional study 94,95 . However, while genome editing constitutes an important tool to study the effects of whole pharmacogene knockout in animals, most commonly mice [96][97][98][99] , application of such methods to study point mutations, especially those that are rare, is costand time-inefficient.…”

Macrophage imaging and subset analysis using single-cell RNA sequencing

“…OATP2B1 mediates MΦ uptake of the uremic toxin indoxyl sulfate, which is a metabolite of dietary tryptophan and elicits pro-inflammatory signaling and atherosclerosis lesion development in mice [133]. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors including fluvastatin, rosuvastatin, and the antihistamine fexofenadine are OATP2B1 substrates according to recent reports that examined OATP2B1 knockout mouse models [134].…”