Pantoprazol Metabolizmasında Sitokrom P450 Enzimleri 2C19, 3A4, 3A5 ve İlaç Transporteri MDR1’in Genetik Polimorfizmlerinin Etkileri ve Tedavi Yanıtındaki Önemi

Abstract

Pantoprazole inhibits proton pump which is the last phase of the hydrochloric acid generation in stomach. Pantoprazole is metabolised by cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4. It is a substrate of the MDR1 transporter, which affects the distribution of the various drugs in the tissues. Single-nucleotide polymorphisms (SNPs) in the CYP2C19 (*2, *3, *17) and CYP3A4 (*22) and MDR1 (3435C/T, 2677G/T-A) genes affect the enzyme activity and the gene expression. There is no study investigating the effects of CYP3A4 and CYP3A5 genetic polymorphisms on the metabolism of pantoprazole. These genomic changes may affect treatment results. The purpose of this study was to determine the frequencies of the CYP2C19*2, *3, *17, CYP3A4*1B, 1G, *22, CYP3A5*3 and MDR13435C>T, 2677G>T/A genetic polymorphisms and to investigate the association of these polymorphisms with the serum pantoprazole levels, Helicobacter pylori (H.P.) eradication and ulcer treatment. One hundred and ninety-four patients with the diagnosis of Helicobacter pylori (H.P.) gastritis were included in this study. In the first day, a single oral dose of pantoprazole (40 mg) was given to patients for the phenotyping of CYP2C19 and blood sample has been taken after 3 hours. Plasma levels of pantoprazole were analyzed by high pressure liquid chromatography (HPLC) method. Genotyping was done by polymerase chain reaction, endonuclease restriction (PCR-RFLP) methods and sequencing. H.P. eradication was determined by fecal H.P. antigen six weeks after the end of the treatment. One hundred and five of the 194 patients were reexamined after the drug treatment. In 87 of the patients H.P. antigen was negative (-) and in 18 of the patients H.P. antigen was positive (+). Plasma pantoprazole concentrations of H.P. (-) and (+) patients were measured as 1.9 ± 0.15 μg/ml and 1.7 ± 0.37 μg/ml, respectively (p=0.45). Patient groups determined according to the CYP2C19 and CYP3A4 genotypes had no significant difference in the H.P. eradication rate (X2=0.28, p=0.86 and X2=1.82, p=0.60). CYP3A5*3 allele was associated with a higher eradication rate (X2=6.92, p=0.03). In the MDR1 3435C/T and 2677G/T-A haplotype groups, eradication rates of patients with TT-TT (n=26) genotype were significantly higher than that of the patients with CC-GG (n=12) genotype (X2=4.48, p=0.01). 194 patients were grouped according to predicted metabolic rate. Pantoprazole plasma concentrations of ultra rapid metabolizer (URM, n=53) (*1*17 and *17*17), rapid metabolizer (RM, n=90) (*1*1) and poor metabolizer (PM, n=37) (*1*2, *1*3 and *2*2) groups were 1.39±0.15; 1.80±0.15; 2.16±0.27 μg/ml, respectively. The difference between URM and PM groups was significant (p=0.03). CYP3A4, CYP3A5 and MDR1 genetic polymorphisms did not significantly affect the plasma pantoprazole concentration. In conclusion, although, the CYP2C19 genetic polymorphisms affect the plasma pantoprazole concentration, this effect does not alter response of the treatment of peptic ulcer. MDR1 TT-TT genotype and CYP3A5 * 3 allele has been associated with a higher eradication rate. Key words: Cytochrome P450 2C19, 3A4 and 3A5, MDR1, genetic polymorphism, pantoprazole, genotyping, phenotyping, Helicobacter pylori, peptic ulcer This thesis work was supported by “Hacettepe University Scientific Research Unit” (013 D10 101 001).