Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor metabolizers.
Lansoprazole is a potent gastric proton pump inhibitor that is metabolized by CYP2C19 but appears to induce the activity of hepatic microsomal CYP1A2 in a concentration-dependent manner. Because the inducing effect appears to be a dose-dependent phenomenon, it may be more important in poor metabolizers of CYP2C19 who have more than four times the area under the lansoprazole plasma concentration-time curve (AUC) and constitute 12% to 23% of Asian populations. Theophylline owes a significant portion of its metabolism to CYP1A2 and can cause gastric acid reflux that calls for concurrent use of proton pump inhibitors. We conducted a prospective, randomized, subject-blind, multicenter crossover study of the effect of multiple high-dose oral lansoprazole (30 mg twice a day for 7 days) on the pharmacokinetics of a single intravenous dose of theophylline (4.73 mg/kg) in healthy volunteers characterized for CYP2C19 genotype. The study compared the pharmacokinetics of lansoprazole and theophylline in five white extensive metabolizers, six Korean extensive metabolizers, and seven poor metabolizers of CYP2C19. The pharmacokinetics of lansoprazole were significantly different among groups; AUC values were 1.55+/-0.20 microg x h/mL in white extensive metabolizers, 7.01+/-0.72 microg x hr/mL in Korean extensive metabolizers, and 14.34+/-2.60 microg x h/mL in poor metabolizers (P < .001). The administration of lansoprazole did not change intravenous theophylline clearance compared with placebo in any group, and theophylline clearance exhibited no correlation with AUC of lansoprazole (rs = 0.12; P > .1). These data suggest that usual therapeutic doses of lansoprazole have no clinically significant influence on the clearance of theophylline, even in poor metabolizers of CYP2C19.
Ko
J W
JW
Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA.
Jang
I J
IJ
Shin
J G
JG
Nam
S K
SK
Shin
S G
SG
Flockhart
D A
DA
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People / Q000235:genetics; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006801:Humans; D064747:Lansoprazole; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D017494:Proton Pumps / Q000187:drug effects; D012016:Reference Values; D016037:Single-Blind Method; D013806:Theophylline / Q000493:pharmacokinetics*; D013997:Time Factors; D014838:Volunteers; D044465:White People / Q000235:genetics
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001993:Bronchodilator Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017494:Proton Pumps; D064747:Lansoprazole; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole