Abstract
To assess the effects of intestinal cytochrome P450 2C19 on the interaction between tacrolimus and proton pump inhibitors, we examined the concentration/dose ratio [(ng/ml)/(mg/day)] of tacrolimus coadministered with omeprazole (20 mg) or lansoprazole (30 mg) to 89 adult living-donor liver transplant patients on postoperative days 22 to 28, considering the CYP2C19 genotypes of the native intestine and the graft liver, separately. The concentration/dose ratio of tacrolimus coadministered with omeprazole was significantly higher in patients with two variants (*2 or *3) for intestinal CYP2C19 (median, 6.38; range, 1.55–22.9) than intestinal wild-type homozygotes (median, 2.11; range, 1.04–2.54) and heterozygotes (median, 2.11; range, 0.52–4.33) (P = 0.010), but the extent of the increase was attenuated by carrying the wild-type allele in the graft liver even when patients were CYP3A5*1 noncarriers. Conversely, the CYP2C19 polymorphisms both in the native intestine and in the graft liver little influenced the interaction between tacrolimus and lansoprazole, but CYP3A5*1 noncarriers showed higher tacrolimus concentration/dose ratio than CYP3A5*1 carriers. Furthermore, our experiments in vitro revealed that lansoprazole had a stronger inhibitory effect on the CYP3A5-mediated metabolism of tacrolimus than omeprazole, although not significantly (IC50 = 19.9 ± 13.8 μM for lansoprazole, 53.7 ± 6.1 μM for omeprazole). Our findings suggest that intestinal and graft liver CYP2C19 plays a relatively greater role in the metabolism of omeprazole than it does for lansoprazole, so that the effects of CYP3A5 on the metabolism of tacrolimus might be masked by the interaction with omeprazole associated with the CYP2C19 genotype.
Footnotes
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This work was supported in part by the 21st Century Center of Excellence (COE) Program “Knowledge Information Infrastructure for Genome Science”; a grant-in-aid from the Japan Health Sciences Foundation for “Research on Health Sciences Focusing on Drug Innovation”; and a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.025833.
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ABBREVIATIONS: P450, cytochrome P450; PPI, proton pump inhibitor; PM, poor metabolizer; IM, intermediate metabolizer; EM, extensive metabolizer; LDLT, living-donor liver transplantation; C/D, concentration/dose; M-I, 13-O-demethyl tacrolimus.
- Received November 24, 2008.
- Accepted January 8, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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