Abstract
The hepatobiliary disposition of xenobiotics may involve passive and/or active uptake, metabolism by cytochromes P450, and excretion of the parent compound and/or metabolite(s) into bile. Although in vitro systems have been used to evaluate these individual processes discretely, mechanistic in vitro studies of the sequential processes of uptake, metabolism, and biliary or basolateral excretion are limited. The current studies used sandwich-cultured (SC) rat hepatocytes combined with a comprehensive pharmacokinetic modeling approach to investigate the hepatobiliary disposition of terfenadine and fexofenadine, a model drug/metabolite pair. The metabolism of terfenadine and the biliary excretion of terfenadine and fexofenadine were determined in control and dexamethasone-treated SC rat hepatocytes. Dexamethasone (DEX) treatment increased the formation rates of the terfenadine metabolites azacyclonol and fexofenadine ∼20- and 2-fold, respectively. The biliary excretion index (BEI) of fexofenadine, when generated by terfenadine metabolism, was not significantly different from the BEI of preformed fexofenadine (15 ± 2% versus 19 ± 2%, respectively). Pharmacokinetic modeling revealed that the rate constant for hepatocyte uptake was faster for terfenadine compared with preformed fexofenadine (2.5 versus 0.08 h-1, respectively), whereas the biliary excretion rate constant for preformed fexofenadine exceeded that of terfenadine (0.44 versus 0.039 h-1, respectively). Interestingly, the rate constants for basolateral excretion of terfenadine and fexofenadine were comparable (3.2 versus 1.9 h-1, respectively) and increased only slightly with DEX treatment. These studies demonstrate the utility of the SC hepatocyte model, coupled with pharmacokinetic modeling, to evaluate the hepatobiliary disposition of generated metabolites.
Footnotes
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This research was supported by Pfizer Global Research and Development and National Institutes of Health Grant RO1 GM41935.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102616.
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ABBREVIATIONS: Oatp/OATP, organic anion transporting polypeptide; Mrp/MRP, multidrug resistance-associated protein; SC, sandwich-cultured; DEX, dexamethasone; DMEM, Dulbecco's modified Eagle's medium; HBSS, Hanks' balanced salt solution; BEI, biliary excretion index; BC, bile-canaliculi; HPLC, high-performance liquid chromatography; LC/MS/MS, liquid chromatography/tandem mass spectrometry; ClB in vitro, in vitro biliary clearance; AUC, area under the curve; TER, terfenadine; FEX, fexofenadine; AZA, azacyclonol; pre, preformed; gen, generated.
- Received February 15, 2006.
- Accepted May 9, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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