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Dronedarone biodistribution in hyperlipidemia and dronedarone metabolism in hyperlipidemia or obesity were assessed. Male Sprague–Dawley rats were given either normal standard chow with water or various high-fat or high-carbohydrate diets for 14 weeks. There was also a nonobese hyperlipidemic group given poloxamer 407 intraperitoneally. Liver and intestinal microsomes were prepared and the metabolic conversion of dronedarone to desbutyldronedarone was followed. A biodistribution study of dronedarone given orally was conducted in hyperlipidemic and control normolipidemic rats. The metabolism of dronedarone to desbutyldronedarone in control rats was consistent with substrate inhibition. However in the treatment groups, the formation of desbutyldronedarone did not follow substrate inhibition; hyperlipidemia and high-calorie diets created remarkable changes in dronedarone metabolic profiles and reduction in formation velocities. Tissue concentrations of dronedarone were much higher than in plasma. Furthermore, in hyperlipidemia, plasma and lung dronedarone concentrations were significantly higher compared to normolipidemia.

IntroductionTestosterone is a well‐established probe substrate for assessing functional levels of cytochrome P450 (CYP) 3A4‐mediated metabolism. Parenteral testosterone replacement therapy is commonly prescribed for male hypogonadism, given the low oral bioavailability of oral testosterone. However, some investigators are exploring the oral delivery of testosterone or its esters using specialized formulations that might promote lymphatic intestinal absorption. Exogenous administration of hormones is known to down‐regulate endogenous production, which could lead to less than expected increases in exposure with repeated administration, but other factors such as self‐induction of metabolism could also contribute. There is little if any substantive information available that sheds light on whether or not testosterone has any inductive effects on CYP3A4 mediated metabolism, or on any other CYP isoforms. The intent of this study was to use intestinal and hepatic human cell lines to assess for possible induction of CYP3A4 and CYP1A1.MethodsHuman hepatic (HepG2) and colonic/intestinal (Lovo) cell lines were grown in 12 well plates and spiked with testosterone (300, 3000 or 30000 ng/dL once or twice daily for 3 days). Control cells were similarly treated with matching media minus testosterone. At the end of the 3 days of treatment, some cells were used to measure mRNA and protein for CYP1A1, CYP3A4, and multidrug resistance protein (MDR1). In addition, the effect of testosterone pretreatment on its own in vitro clearance, and CYP1A1–specific functional activity (using 7‐ethoxyin O‐deethylase activity) were also tested in the cell lines.ResultsBased on the mRNA and protein measures, there was no evidence of a testosterone‐related change in protein expression of the target genes or housekeeping genes. Functional studies indicated no change in CYP1A1 activity. Using a LC‐MS assay method, the cells lines displayed a rapid decrease in testosterone concentrations; it was established that there was no binding of testosterone to the plastic well plates used in the studies. HepG2 cells preexposed with 3000 ng/dL twice daily testosterone for 3 d had no associated changes in testosterone clearance after the testosterone preexposure phase. In the Lovo cells, testosterone pretreatment with 30000 ng/dL of testosterone was associated with an apparent inhibition in vitro of testosterone clearance. The testosterone concentrations exposed to intestinal cells were higher than liver cells because enterocyte exposure after oral administration would be expected to greatly exceed those in the liver.ConclusionThere was no evidence for induction of testosterone metabolism in vitro using human liver and intestinal cell lines. The decrease in testosterone clearance in the intestinal cells after preexposure might have been due to accumulation of metabolites, with a pursuant competitive or noncompetitive inhibition of testosterone metabolism.Support or Funding InformationFunding provided by TesoRx Pharma LLCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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