Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data.
BACKGROUND
The clinical outcome of acid-related disorders treated by proton pump inhibitors (PPIs) might be dependent on the polymorphically expressed cytochrome P450 (CYP) 2C19, which is involved in PPI metabolism. We tested whether esomeprazole-induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype.


METHODS
Two hundred five patients with GERD (Los Angeles classification grade A or B) were included in a case-control study according to endoscopic outcome (healed versus unhealed group, matched for confounders) after treatment with 40 mg esomeprazole daily for 4 weeks. The frequency of CYP2C19 genotypes was determined as the primary outcome measure for both groups. In a second trial plasma levels of esomeprazole and corresponding CYP2C19 and CYP3A4 metabolites (5-hydroxyomeprazole and omeprazole sulfone) were monitored in 10 CYP2C19 wild-type patients with GERD after the first and last doses (day 7) of 40 mg esomeprazole daily to calculate metabolic ratios.


RESULTS
CYP2C19 wild-type (n = 148) and heterozygous (n = 51) or homozygous variant (n = 6) patients did not differ with respect to baseline characteristics. The frequency distribution of CYP2C19 genotypes was not different between patients with complete (75/100) and incomplete (73/105) healing (P = .65). When a single esomeprazole dose and multiple dosing were compared, the low contribution of CYP2C19 to the elimination of esomeprazole decreased further by 50%. In contrast, the CYP3A4-dependent formation of omeprazole sulfone increased by 40%, and consequently, the metabolic ratio of omeprazole sulfone to 5-hydroxyomeprazole was elevated from 7.9 to 19.3 (P = .0004).


CONCLUSIONS
In contrast to other PPIs, esomeprazole-induced healing of GERD is unrelated to the CYP2C19 genotype, which can be explained by the metabolic shift toward the CYP3A4-mediated pathway.
Schwab
Matthias
M
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. mattias.schwab@stjude.org
Klotz
Ulrich
U
Hofmann
Ute
U
Schaeffeler
Elke
E
Leodolter
Andreas
A
Malfertheiner
Peter
P
Treiber
Gerhard
G
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D064098:Esomeprazole / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives; D011446:Prospective Studies; D054328:Proton Pump Inhibitors; D013997:Time Factors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; C040450:omeprazole sulfone; D003577:Cytochrome P-450 Enzyme System; C049963:5-hydroxymethylomeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole; D064098:Esomeprazole