Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes.
OBJECTIVE
To examine the enzyme kinetics of gefitinib and erlotinib metabolism by individual cytochrome P450 (CYP) enzymes, and to compare their effects on CYP3A activity, with the aim to better understand mechanisms underlying pharmacokinetic variability and clinical effects.


METHODS
Enzyme kinetics were examined by incubating gefitinib or erlotinib (1.5-50 micromol/L) with recombinant human CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, and CYP1B1 (10-160 pmol/mL). Their effects on CYP3A activity were examined by comparing midazolam metabolism in the presence and absence of gefitinib or erlotinib in human liver and intestinal microsomes. Parent compounds and metabolites were monitored by high-performance liquid chromatography with a photodiode detector or tandem mass spectrometer.


RESULTS
Both drugs were metabolized primarily by CYP3A4, CYP3A5, and CYP1A1, with respective maximum clearance (Cl(max)) values for metabolism of 0.41, 0.39, and 0.57 mL/min/nmol for gefitinib and 0.24, 0.21, 0.31 mL/min/nmol for erlotinib. CYP2D6 was involved in gefitinib metabolism (Cl(max), 0.63 mL/min/nmol) to a large extent, whereas CYP1A2 was considerably involved in erlotinib metabolism (Cl(max), 0.15 mL/min/nmol). Both drugs stimulated CYP3A-mediated midazolam disappearance and 1-hydroxymidazolam formation in liver and intestinal microsomes.


CONCLUSIONS
Gefitinib is more susceptible to CYP3A-mediated metabolism than erlotinib, which may contribute to the higher apparent oral clearance observed for gefitinib. Metabolism by hepatic and extrahepatic CYP1A may represent a determinant of pharmacokinetic variability and response for both drugs. The differential metabolizing enzyme profiles suggest that there may be differences in drug-drug interaction potential and that stimulation of CYP3A4 may likely play a role in drug interactions for erlotinib and gefitinib.
Li
Jing
J
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Zhao
Ming
M
He
Ping
P
Hidalgo
Manuel
M
Baker
Sharyn D
SD
D018686:Anesthetics, Intravenous / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000378:metabolism* / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000378:metabolism
D018686:Anesthetics, Intravenous; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D000069347:Erlotinib Hydrochloride; D008874:Midazolam; D000077156:Gefitinib