TY - JOUR
T1 - In silico and in vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer
AU - Maréchal, Jean Didier
AU - Yu, Jinglei
AU - Brown, Simon
AU - Kapelioukh, Iouri
AU - Rankin, Elaine M.
AU - Wolf, C. Roland
AU - Roberts, Gordon C K
AU - Paine, Mark J I
AU - Sutcliffe, Michael J.
PY - 2006/4
Y1 - 2006/4
N2 - 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 (r2 = 0.75-0.66) between predicted affinity and our measured IC50 values, and loperamide was confirmed as a potent inhibitor (IC50 of 0.050 ± 0.006 μM). 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 ∼12-fold increase in KM 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. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.
AB - 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 (r2 = 0.75-0.66) between predicted affinity and our measured IC50 values, and loperamide was confirmed as a potent inhibitor (IC50 of 0.050 ± 0.006 μM). 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 ∼12-fold increase in KM 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. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.
U2 - 10.1124/dmd.105.007625
DO - 10.1124/dmd.105.007625
M3 - Article
SN - 1521-009X
VL - 34
SP - 534
EP - 538
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 4
ER -