Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s
Language: 
English
Abstract: 

In this study we have evaluated the application and reliability of using fluorescence (FLUO)-based high throughput screening assays with recombinant CYPs (rCYP). This was accomplished by screening 29 clinically important antiparasitic drugs for inhibition of the five major drug-metabolizing CYPs (-1A2, -2C9, -2C19, -2D6, and -3A4). Data from FLUO/rCYP assays were compared with that obtained by conventional HPLC assays using human liver microsomes (HLM) and rCYPs. The K(i) values showed good correlations: FLUO/rCYP and HPLC/rCYP (r(2) = 0.81), HPLC/rCYP and HPLC/HLM (r(2) = 0.82), and FLUO/rCYP and HPLC/HLM (r(2) = 0.72). Niclosamide had substrate-dependent contrasting effects on CYP2C9 activity with an apparent activation (400%) of 7-methoxy-4-trifluoromethylcoumarin demethylase activity and potent inhibition (K(i) = 6.00 microM) of diclofenac 4-hydroxylase activity. Potent inhibitors of CYP1A2 were artemisinin, dihydroartemisinin, thiabendazole, primaquine, and niclosamide (K(i) = 0.43, 3.67, 1.54, 0.22, and 2.70 microM, respectively). Proguanil, cycloguanil, amodiaquine, and desethylamodiaquine inhibited CYP2D6 (K(i) = 6.76, 5.97, 2.1, and 4.13 microM, respectively). Considering the C(max) of these drugs, artemisinin, thiabendazole, primaquine, amodiaquine, and desethylamodiaquine may cause clinically important interactions because they are predicted to inhibit 67 to 99% of the activities of the CYPs they interact with. In addition, our results suggest CYP1A2 inhibition as the mechanism behind the observed thiabendazole/theophylline and primaquine/antipyrine interactions in vivo.

Author(s): 
Bapiro, T. E.
Egnell, A. C.
Hasler, J. A.
Masimirembwa, C. M.
Item Type: 
Journal Article
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals
Journal Abbreviation: 
Drug Metab. Dispos.
Publication Date: 
1/1/2015
Publication Year: 
2001
Pages: 
30-35
Volume: 
29
Issue: 
1
ISSN: 
0090-9556
Library Catalog: 
PubMed
Extra: 
PMID: 11124226

Turabian/Chicago Citation

T. E. Bapiro, A. C. Egnell, J. A. Hasler and C. M. Masimirembwa. 1/1/2015. "Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s." Drug Metabolism and Disposition: The Biological Fate of Chemicals 29: 1: 30-35.

Wikipedia Citation

<ref> {{Cite journal | doi = | issn = 0090-9556 | volume = 29 | pages = 30-35 | last = Bapiro | first = T. E. | coauthors = Egnell, A. C., Hasler, J. A., Masimirembwa, C. M. | title = Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s | journal = Drug Metabolism and Disposition: The Biological Fate of Chemicals | date = 1/1/2015 | pmid = | pmc = }} </ref>