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Research ArticleArticle

Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 vs. Neonatal Cytochrome P450 3A7

Malika P. Godamudunage, Anne M. Grech and Emily E Scott
Drug Metabolism and Disposition July 10, 2018, dmd.118.082032; DOI: https://doi.org/10.1124/dmd.118.082032
Malika P. Godamudunage
University of Michigan
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Anne M. Grech
University of Michigan
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Emily E Scott
University of Michigan
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  • For correspondence: scottee@umich.edu
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Abstract

Adult drug metabolism is dominated by cytochrome P450 3A4 (CYP3A4), which is often inhibited by antifungal azole drugs, resulting in potential alterations in drug metabolism and adverse drug/drug interactions. In the fetal and neonatal stages of life, expression of CYP3A4 is replaced by the 87%-identical cytochrome P450 3A7 (CYP3A7). Azole antifungals developed for adults are also used in neonates assuming they interact similarly with both enzymes, but systematic information is lacking. Herein a method was developed for generating recombinant purified CYP3A7. Thirteen different azoles were then evaluated for binding and inhibition of purified human CYP3A4 vs. CYP3A7. All imidazole-containing azoles bound both enzymes via coordination to the heme iron and inhibited both with IC50 values ranging from 180 nM for clotrimazole to the millimolar range for imidazole itself. Across this wide range of potencies, CYP3A4 was consistentely inhibited more strongly than CYP3A7, with clotrimazole being the least selective (1.5-fold) inhibitor and econazole the most selective (12-fold). Observations for 1,2,4-triazole-containing azoles were more varied. Most bound to CYP3A4 via coordination to the heme iron, but several also demonstrated evidence of a distinct binding mode at low concentrations. However, only posaconazole inhibited CYP3A4. Similarly, only posaconazole inhibited CYP3A7, again less potently than CYP3A4, with spectral evidence for binding weak or nonexistent for all triazoles. Overall, while the details of binding interactions do vary, the same azole compounds inhibit both enzymes, albeit with weaker interactions with CYP3A7 compared to CYP3A4.

  • cytochrome P450
  • enzyme inhibitors
  • fetal drug metabolism
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 47 (12)
Drug Metabolism and Disposition
Vol. 47, Issue 12
1 Dec 2019
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Research ArticleArticle

Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 vs. Neonatal Cytochrome P450 3A7

Malika P. Godamudunage, Anne M. Grech and Emily E Scott
Drug Metabolism and Disposition July 10, 2018, dmd.118.082032; DOI: https://doi.org/10.1124/dmd.118.082032

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Research ArticleArticle

Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 vs. Neonatal Cytochrome P450 3A7

Malika P. Godamudunage, Anne M. Grech and Emily E Scott
Drug Metabolism and Disposition July 10, 2018, dmd.118.082032; DOI: https://doi.org/10.1124/dmd.118.082032
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