Gefitinib-phenytoin interaction is not correlated with the C-erythromycin breath test in healthy male volunteers.
OBJECTIVE
We aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate.


METHODS
An open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg(-1) daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the (14)C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively.


RESULTS
Following treatment with phenytoin, mean gefitinib C(max) and AUC(0-infinity) decreased by 26 +/- 44% [95% confidence interval (CI) for the difference 5-48%, P= 0.005] and 47 +/- 26% (95% CI for the difference 34-60%, P= 0.001), respectively, and apparent oral clearance increased by 126 +/- 93% (95% CI for the difference 80-172%, P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 +/- 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase.


CONCLUSIONS
The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.
Chhun
Stephanie
S
Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, 75475 Paris Cedex 10, France.
Verstuyft
Celine
C
Rizzo-Padoin
Nathalie
N
Simoneau
Guy
G
Becquemont
Laurent
L
Peretti
Ilana
I
Swaisland
Alan
A
Wortelboer
Robert
R
Bergmann
Jean Francois
JF
Mouly
Stephane
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001944:Breath Tests; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions / Q000235:genetics; D004812:Epidemiologic Methods; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D010672:Phenytoin; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077156:Gefitinib
J Natl Cancer Inst. 2006 Dec 6;98(23):1714-23
17148773
J Clin Oncol. 2005 Dec 20;23(36):9265-74
16361624
Clin Cancer Res. 2000 Apr;6(4):1255-8
10778948
J Clin Invest. 1999 Jul;104(2):147-53
10411543
Drug Metab Dispos. 2006 May;34(5):880-6
16467132
Clin Pharmacol Ther. 1998 Jul;64(1):129-30
9695728
Antimicrob Agents Chemother. 2001 Feb;45(2):502-8
11158747
Invest New Drugs. 2006 Jul;24(4):291-7
16502356
Clin Pharmacol Ther. 1998 Sep;64(3):248-56
9757148
Br J Clin Pharmacol. 2006 Aug;62(2):200-9
16842395
Clin Pharmacol Ther. 2001 Jan;69(1):14-23
11180034
Crit Rev Oncol Hematol. 2005 Aug;55(2):117-42
15890526
Lancet. 2000 Jul 22;356(9226):285-90
11071183
Clin Pharmacol Ther. 1994 Sep;56(3):253-60
7924120
Proc Natl Acad Sci U S A. 1987 Jan;84(1):265-9
2432605
Clin Pharmacokinet. 2006;45(6):633-44
16719544
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473-8
10716719
Clin Lung Cancer. 2003 Sep;5 Suppl 1:S18-21
14641990
J Pharm Sci. 1995 Mar;84(3):292-4
7616365
Cancer Biol Ther. 2007 Mar;6(3):432-8
17312388
Br J Clin Pharmacol. 2002 Dec;54(6):610-6
12492608
Pharmacogenetics. 1996 Aug;6(4):351-5
8873221
Drug Metab Dispos. 2000 Jul;28(7):766-71
10859150
Mol Carcinog. 1995 Jul;13(3):129-34
7619215
Xenobiotica. 2005 Jan;35(1):39-50
15788367
Clin Cancer Res. 2004 Feb 15;10(4):1212-8
14977817
J Pharm Biomed Anal. 2002 Jun 20;29(1-2):221-8
12062681
Clin Pharmacokinet. 2005;44(11):1165-77
16231967
Xenobiotica. 2006 Jan;36(1):29-39
16507511
Clin Pharmacol Ther. 1997 May;61(5):531-43
9164415
Pharmacogenetics. 1994 Aug;4(4):171-84
7987401
Pharmacogenomics J. 2007 Jun;7(3):154-79
16969364
Ther Drug Monit. 2005 Jun;27(3):305-8
15905800
J Clin Pharm Ther. 2004 Apr;29(2):95-103
15068398
Lancet Neurol. 2003 Jul;2(7):404-9
12849118
Curr Drug Deliv. 2004 Jan;1(1):27-42
16305368
Clin Pharmacol Ther. 2001 Sep;70(3):217-27
11557909
Clin Pharmacol Ther. 2009 Feb;85(2):155-63
18509327
Lung Cancer. 2005 Sep;49(3):337-43
15955594
J Am Soc Nephrol. 2003 Jul;14(7):1889-96
12819250
Lancet. 2002 Jan 5;359(9300):30-6
11809184
Clin Pharmacokinet. 2005;44(10):1067-81
16176119
Clin Pharmacol Ther. 2007 Jun;81(6):828-32
17361125
Clin Pharmacol Ther. 2006 Sep;80(3):228-34
16952489
J Pharmacol Exp Ther. 1994 Oct;271(1):557-66
7965756
Environ Health Perspect. 1995 Jun;103 Suppl 5:25-8
8565903
Mol Pharmacol. 2004 Jun;65(6):1485-95
15155841
Xenobiotica. 2004 Nov-Dec;34(11-12):983-1000
15801543
Clin Pharmacol Ther. 1995 Jul;58(1):20-8
7628179
Am J Hum Genet. 1997 Feb;60(2):284-95
9012401
Xenobiotica. 2004 Oct;34(10):917-34
15764411
J Natl Cancer Inst. 2006 Dec 6;98(23):1739-42
17148776
Clin Pharmacol Ther. 2002 Jul;72(1):1-9
12151999
Curr Neurovasc Res. 2008 May;5(2):82-92
18473823
Clin Cancer Res. 2004 Jul 15;10(14):4607-13
15269131
Int J Clin Pharmacol Ther. 1998 Mar;36(3):126-32
9562227