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Open Access Reversible inhibition of four important human liver cytochrome P450 enzymes by diethylstilbestrol

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Diethylstilbestrol (DES), a synthetic estrogen clinically used to treat threatened abortion between the 1940 s and the 1970 s, has been restricted to treat certain cases of prostatic and breast cancer due to its adverse drug responses such as teratogenicity and carcinogenicity. Some reports have demonstrated that the addition of DES to docetaxel could modify tubulin composition and improve response of prostate cancer to chemotherapy. Given that DES might be co-administered with other drugs such as docetaxel, the present study focused on CYP-based drug-drug interaction (DDI). In vitro inhibitory effects of DES on CYP isoforms were investigated, and the results showed that DES could competitively inhibit CYP3A4, CYP2C8, CYP2C9 and CYP2E1. The inhibition constants (Ki) were calculated to be 4.4 M, 3.0 M, 5.0 M and 8.0 M for CYP3A4, CYP2C9, CYP2E1 and CYP2C8, respectively. Based on peak serum DES level after drip influsion of 500 mg of fosfestrol (DES diphosphate) in patients, [I]/Ki was calculated to be 4.3, 6.2, 3.7 and 2.3 for CYP3A4, CYP2C9, CYP2E1 and CYP2C8, which suggested that DES was likely to induce in vivo DDI through inhibition of these four major CYP isoforms. These results collectively demonstrate that adverse drug responses might exist when DES is co-administered with other drugs.
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Document Type: Research Article

Publication date: 01 March 2011

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  • Pharmazie is a leading journal in the field of pharmaceutical sciences. As a peer-reviewed scientific journal, Pharmazie is regularly indexed in the relevant databases like Web of science, Journal Citation Reports and many others. The journal is open for submissions from the whole spectrum of pharnaceutical sciences including Pharmaceutical Chemistry, Experimental and Clinical Pharmacology, Drug Analysis, Pharmaceutics, Pharmaceutical Biology, Clinical Pharmacy etc.
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