In silico and in vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer.
Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for phase I drug metabolism of many anticancer agents. It is also a major route for metabolism of many drugs used by patients to treat the symptoms caused by cancer and its treatment as well as their other illnesses, for example, cardiovascular disease. To assess the ability to inhibit CYP3A4 of drugs most commonly used by our patients during cancer therapy, we have made in silico predictions based on the crystal structures of CYP3A4. From this set of 33 common comedicated drugs, 10 were predicted to be inhibitors of CYP3A4, with the antidiarrheal drug loperamide predicted to be the most potent. There was significant correlation (r(2) = 0.75-0.66) between predicted affinity and our measured IC(50) values, and loperamide was confirmed as a potent inhibitor (IC(50) of 0.050 +/- 0.006 microM). Active site docking studies predicted an orientation of loperamide consistent with formation of the major (N-demethylated) metabolite, where it interacts with the phenylalanine cluster and Arg-212 and Glu-374; experimental evidence for the latter interaction comes from the approximately 12-fold increase in K(M) for loperamide observed for the Glu-374-Gln mutant. The commonly prescribed drugs loperamide, amitriptyline, diltiazem, domperidone, lansoprazole, omeprazole, and simvastatin were identified by our in silico and in vitro screens as relatively potent inhibitors of CYP3A4 that have the potential to interact with cytotoxic agents to cause adverse effects, highlighting the likelihood of drug-drug interactions affecting chemotherapy treatment.
Marechal
Jean-Didier
JD
School of Chemical Engineering and Analytical Science, University of Manchester, The Mill, PO Box 88, Manchester, M60 1QD, UK.
Yu
Jinglei
J
Brown
Simon
S
Kapelioukh
Iouri
I
Rankin
Elaine M
EM
Wolf
C Roland
CR
Roberts
Gordon C K
GC
Paine
Mark J I
MJ
Sutcliffe
Michael J
MJ
D000930:Antidiarrheals / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008139:Loperamide / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000930:Antidiarrheals; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D008139:Loperamide; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human