FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS

Transporters play a major role in the absorption and disposition of fexofenadine, suggesting this drug could be used as a probe of transporter activity. When fexofenadine was administered in combination with four drugs (buspirone, caffeine, dextromethorphan and losartan) used to probe cytochrome P450 (CYP) activities, a significant decrease in fexofenadine AUC was observed without a change in elimination. Based on this observation, I hypothesized a fexofenadine-probe drug interaction was occurring during oral absorption, and that this interaction was occurring at an enterocyte-expressed OATP. This interaction was reproduced and studied using in vitro model systems. In Specific Aim 1, a specific LC-MS/MS method was developed and validated for the quantification of fexofenadine and the other four probe drugs for use in the remaining specific aims. In Specific Aim 2, the interaction between fexofenadine and four enterocyte- and hepatocyte-expressed OATPs was characterized, and OATP1A2 was identified as the most effective transporter of fexofenadine, with a Km of 35 μM. Because fexofenadine was efficiently transported by OATP1A2, the four CYP probe drugs were tested as inhibitors of OATP1A2-mediated fexofenadine transport in Specific Aim 3. Buspirone, losartan, and dextromethorphan each inhibited OATP1A2-mediated fexofenadine transport in a concentration dependent manner. This inhibition could explain the decrease in fexofenadine oral bioavailability seen in the clinical study we had previously conducted. The replication of the fexofenadine-probe drug interaction in this model system supports the conclusion that OATP1A2 is the major uptake transporter for fexofenadine absorption in the enterocyte, and suggests that fexofenadine may be an effective probe drug for this transporter. In Specific Aim 4, I further characterized the fexofenadine-probe drug interactions using the three known OATP1A2 polymorphisms: Ile13Thr, Arg168Cys, and Glu172Asp. While the mutants functioned as expected with regard to fexofenadine transport, the presence of the mutation did not alter the observed drug-drug interactions seen previously with OATP1A2 and the CYP probes. Taking these data into account, it appears the fexofenadine-drug interaction seen previously is not affected by single nucleotide polymorphisms. This work demonstrates that OATP1A2 is capable of transporting fexofenadine and that several CYP probe drugs inhibit its transport by OATP1A2. This latter observation limits the utility of fexofenadine to be used as a single probe, rather than as part of a probe drug cocktail.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2011

Author dc:creator

• Flynn, Colleen A.

Advisor dc:contributor.advisor

• Reed, Gregory A

• Toxicology
• Drug-drug interactions
• Fexofenadine
• Oatp
• Probe cocktail
• Single nucleotide polymorphism

Statement dc:rights

• This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:11845

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/9723