Open AccessEffect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations
Author(s) -
Itagaki Fumio,
Homma Masato,
Yuzawa Kenji,
Nishimura Masuhiro,
Naito Shinsaku,
Ueda Nobuhiko,
Ohkohchi Nobuhiro,
Kohda Yukinao
Publication year - 2004
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1211/0022357043914
Subject(s) - lansoprazole , tacrolimus , cyp2c19 , rabeprazole , pharmacokinetics , pharmacology , proton pump inhibitor , cyp3a5 , cmax , crossover study , medicine , chemistry , omeprazole , genotype , gastroenterology , transplantation , cytochrome p450 , biochemistry , metabolism , alternative medicine , pathology , gene , placebo
The aim of this study was to investigate the effects of the proton pump inhibitors (PPIs), lansoprazole and rabeprazole, on tacrolimus pharmacokinetics in healthy volunteers with mutations in the cytochrome P450 (CYP) 2C19 gene ( CYP2C19 ). An open‐label crossover study was performed with 19 healthy subjects. Tacrolimus (2 mg) was administered orally with and without lansoprazole (30 mg per day for 4 days) or rabeprazole (10 mg per day for 4 days). Blood concentrations of tacrolimus were determined before and 1, 2, 4 and 8 h after dosing. Genotyping for CYP2C19 was conducted by a polymerase chain reaction‐restriction fragment length polymorphism method. Coadministration of lansoprazole significantly decreased the oral tacrolimus clearance, resulting in an increase in the area under the blood concentration‐time curve (AUC 0–8 ) (control vs with lansoprazole: 29.7 ± 3.5 vs 44.1 ± 5.0 ng h mL −1 , P <0.05). Large individual variation was observed in the effects of lansorazole on tacrolimus AUC 0–8 owing to CYP2C19 genotype status. The percent change for tacrolimus AUC 0–8 in subjects with and without CYP2C19 mutant alleles was 81% and 29%, respectively. Coadministration of rabeprazole also increased the mean AUC 0–8 of tacrolimus, but the difference was not statistically significant. These observations suggest that drug interaction between tacrolimus and lansoprazole occurs in subjects with higher lansoprazole blood concentrations corresponding to CYP2C19 genetic status. In contrast, rabeprazole has minimal effect on tacrolimus pharmacokinetics regardless of CYP2C19 genotype status.