CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers.

OBJECTIVES: Pantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated. METHODS: Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug. RESULTS: Carriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17 genotype (n = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6) displayed concentration-time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ(z)) by 83.3%, prolongation of terminal half-life (t(½)) by 572%, a rise in area under the concentration-time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg·h/L vs 3.00 ± 1.02 mg·h/L, p < 0.05) and C(max) (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p < 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h). CONCLUSION: These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.

Effect of the ADRB1 1165C>G and 145A>G polymorphisms on hemodynamic response during dobutamine stress echocardiography.

PURPOSE: The aim of this study was to determine an association between the ADRB1 1165C>G and 145A>G polymorphisms and hemodynamic response [heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure] to dobutamine during dobutamine stress echocardiography (DSE). METHODS: The study involved 144 patients with clinical indications for DSE. The PCR-restriction fragment length polymorphism method was used to identify the ADRB1 1165C>G and 145A>G polymorphisms. RESULTS: Heart rate during DSE increased in all analyzed study groups. Patients with the ADRB1 1165CC and 1165CG+GG polymorphisms demonstrated similar HR, including magnitude of response [change in heart rate (ΔHR 0-30): 42.1 ± 17.5 vs. 46.1 ± 15.5 bpm, respectively]. HR and ΔHR 0-30 were comparable in ADRB1145AA and 145AG subjects in the course of DSE. SBP and DBP at all stages of DSE were similar in subjects with either polymorphism and did not differentiate patients with the ADRB1 145AA polymorphism from those with the ADRB1 145AG polymorphism, nor those with the ADRB1 1165CC polymorphism from those with the ADRB1 1165CG+GG polymorphism. No differences were noted in the magnitude of response, with the increase in SBP and DBP comparable in all genotypes. Similar observations were made in patients (25/144 studied) with atropine requirements during DSE. CONCLUSION: The ADRB1 1165C>G and 145A>G polymorphisms are not associated with the HR, SBP and DBP responses in Polish Caucasian patients requiring diagnostic dobutamine stress echocardiography.

The SLC19A1 80G>A polymorphism is not associated with male infertility.

Previous studies have revealed that genetic factors may be involved in regulating folate turnover, e.g. methylenetetrahydrofolate reductase polymorphism in the development of male infertility. Folate transporter, encoded by the SLC19A1 gene, commonly referred to as reduced folate carrier (RFC) is a transmembrane protein, which transfers hydrophilic folates across the cell membrane. It was hypothesized that common polymorphism within the SLC19A1 gene (rs1051266:G>A, 80G>A) may alter RFC function. The aim of this study was to investigate a potential association between the SLC19A1 80G>A polymorphism and male infertility in a case-control study. The SLC19A1 80G>A polymorphism was determined by means of a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay in 213 infertile Caucasian men and 226 ethnically matched controls. The distribution of SLC19A1 genotypes in the infertile men was as follows: GG 26.8%, GA 51.2%, AA 22.1% and in fertile men: GG 24.8%, GA 50.4%, AA 24.8%, and was comparable in the both the evaluated groups. Odds ratios (95% confidence interval, CI): 0.90 (0.59-1.38) and 0.88 (0.56-1.36) for dominant and recessive models remained non-significant, also after adjustment for age: 0.89 (0.57-1.37) and 0.80 (0.51-1.25), respectively. Our study demonstrated that polymorphism 80G>A of the SLC19A1 gene is not associated with male infertility.

Association of calpain-10 gene polymorphism and posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus.

New-onset, posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus, and may adversely affect the patient and graft survival. The pathophysiology of PTDM closely mimics that of type II diabetes mellitus (T2DM). One of possible genetic factors predisposing to PTDM might be polymorphism in calpain-10 gene (CAPN10), previously associated with increased risk of T2DM in general population. Therefore, the present study was aimed at evaluation of CAPN10 gene polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. A total of 214 nondiabetic kidney transplant patients medicated with tacrolimus (56 patients with PTDM and 158 patients without PTDM were genotyped for the presence of CAPN10 gene variants (SNP-43: rs3792267:G>A, SNP-19: rs3842570 ins/del and SNP-63: rs5030952:C>T) using PCR-based assays. Frequency of SNP-63 minor allele was slightly increased in PTDM patients (P=0.056), and an association of SNP-63 heterozygosity and the risk of PTDM (odds ratios (OR)=2.45, P=0.023) was observed. An increased odds for PTDM development in patients carrying 1-1-2 haplotype (rs3792267:G-rs3842570:ins-rs5030952:T) compared to noncarriers was also noted (OR=2.35, P=0.026). Patients' higher body mass index and SNP-63 minor T allele carrier status were identified as independent PTDM risk factors, confirmed by multivariate regression analysis. This is the first study of CAPN10 polymorphism in relation to PTDM risk. However, the application of SNP-63 (rs5030952:C>T) as a marker of PTDM should be verified by further independent studies.

Association of the MDR1 (ABCB1) gene 3435C>T polymorphism with male infertility.

Infertility is a common problem affecting one in six couples, and in 30% of infertile couples, the male factor is a major cause due to defective sperm quality. P-glycoprotein (P-gp), a product of the MDR1 (ABCB1) gene, may be a link between genetic and environmental factors contributing to the development of male infertility because pesticides (P-gp substrates) are well established factors of male infertility. The aim of the present study was to examine the effect of the MDR1 gene 3435C>T polymorphism on male infertility. In total, 162 male patients undergoing semen analysis due to initial infertility workup were included in the study. The control group consisted of 191 healthy males with proven fertility. MDR1 3435C>T genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Assessment of MDR1 genotypes among the infertile men showed that 17.9% of subjects were carriers of the CC genotype, 58.0% were CT and 24.1% were TT. Among fertile men, 30.4% of subjects were characterised by the CC genotype, 49.7% were CT and 19.9% were TT. In addition, the frequency of carriers of at least one T allele (i.e., CT and TT genotypes) among infertile and fertile subjects was 82.1% and 69.6%, respectively. The risk of infertility was significantly elevated by two-fold in individuals carrying at least one T allele (CT and TT genotypes: p = 0.009, OR = 2.00, 95% CI: 1.20-3.32). Furthermore, this elevated risk was still found when considering each of the CT and TT genotypes alone (TT genotype: p = 0.027, OR = 2.05, 95% CI: 1.09-3.86; CT genotype: p = 0.013, OR = 1.98, 95% CI: 1.16-3.36). This preliminary report suggests that P-gp may play some role in male infertility, mediating detrimental effects of environmental factors.

Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T polymorphisms and P-glycoprotein inhibitors on salivary digoxin secretion in congestive heart failure patients.

The aim of the present study was to evaluate the effects of ABCB1 ( MDR1 ) gene polymorphism on P-glycoprotein model substrate, i.e. digoxin, salivary secretion. The study was carried out in 77 patients diagnosed with congestive heart failure administered digoxin, who were subdivided into two groups: 1) co-administered P-glycoprotein inhibitors and 2) without any known P-glycoprotein inhibitors. The ABCB1 2677G >A,T and 3435C >T polymorphisms were evaluated using PCR-RFLP methods. Steady-state digoxin concentrations were measured in blood serum as well as in unstimulated and stimulated saliva using FPIA method. It was found that values of Pearson's coefficient were significantly higher in patients co-administered P-glycoprotein inhibitors in comparison with subjects who were not administered any inhibitor both for stimulated (Pearson's coefficient r = 0.832, p < 0.01) and unstimulated saliva (r = 0.812, p < 0.01). Evaluation of the impact of ABCB1 2677G >A,T and 3435C >T polymorphism on salivary digoxin secretion revealed significant differences in digoxin stimulated saliva/serum ratio between patients stratified by 2677G >A,T genotype (TT, TA> GT, GA> GG, p < 0.01). The results from the present study suggest that administration of P-glycoprotein inhibitors as well as ABCB1 gene polymorphism may affect salivary digoxin secretion.

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients.

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.

677C > T and 1298A > C MTHFR polymorphisms affect arechin treatment outcome in rheumatoid arthritis.

Despite the availability of several new agents for the treatment of rheumatoid arthritis (RA), arechin (hydroxychloroquine) remains the mainstay because of both cost-effectiveness and experience with its use. However, there is considerable variation in response to this drug, with toxicity limiting treatment in some patients. Methylenetetrahydrofolate reductase (MTHFR) is involved in the folate metabolism and has been shown to be polymorphic what affects the enzyme activity. To examine the association between 677C > T and 1298A > C MTHFR polymorphisms and arechin efficacy in the treatment of RA, a total of 50 RA patients, treated with arechin were analyzed. In univariate regression analysis model, MTHF R 677T allele was associated with significantly higher frequency of remission, whereas 1298C allele carriers showed a tendency to higher remission rate. In univariate regression analysis model, the presence of MTHFR 677T allele was associated with 2.3-fold higher frequency of remission. Multivariate regression analysis taking into the account the combined effect of MTHFR 677T and 1298C alleles revealed that both alleles were independent factors associated with increased frequency of remission. The results of our study suggest that 677T and 1298C alleles are independent factors associated with increased frequency of remission and the evaluation of C677C > T and A1298A> C MTHFR polymorphisms may be a useful tool to predict arechin treatment outcome in RA patients.

The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs.

OBJECTIVE: Rheumatoid arthritis (RA) is a multifactorial disease, with immunological, genetical as well as environmental factors being implicated in its pathogenesis. Treatment of RA is based mainly on drugs modulating the course of the disease, e.g. methotrexate (MTX) or sulfasalazine (SL). The MDR1 gene product, P-glycoprotein (P-gp), is probably one of the most important and best defined transporters for drug delivery in humans. P-gp transports a wide range of substrates with diverse chemical structures, among them anticancer agents, cardiac drugs, and immunosuppressants. The aim of this study was to examine the effect of the 3435C>T MDR1 gene polymorphism on the efficacy of RA treatment with disease-modifying antirheumatic drugs, i.e. MTX plus methylprednisolone (MP), and SL. METHODS: The study was carried out on 255 patients with RA treated according to two regimes: (1) MTX (7.5-15.0 mg weekly) plus low doses of MP (n=174), (2) SL (1.5-3 g daily, n=81). RESULTS: The probability of remission of RA symptoms after MTX plus MP therapy was 4.65-fold higher in carriers of the TT genotype compared to patients with CC genotype (P=0.003, OR 4.65, 95%CI 1.66-13.05), whereas the probability of remission of RA symptoms in patients treated with SL was 2-fold higher in carriers of TT genotype compared to patients with CC genotype, but did not reach statistical significance (P=0.358, OR=2.00 95% CI=0.58-6.87). CONCLUSION: The results from the present study suggest that the 3435C>T MDR1 gene polymorphism may influence the efficacy of RA therapy with disease-modifying antirheumatic drugs.

Acetylation genotype and phenotype in patients with systemic lupus erythematosus.

UNLABELLED: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting various tissues and organs. In the studies on SLE etiopathogenesis, a potential role of genetically determined impairment of xenobiotic metabolism has been emphasized. N-acetyltransferase 2 enzyme (NAT2) exhibits gene polymorphism and the acetylation rate with NAT2 involvement varies from person to person. The study on acetylation phenotype was carried out using isonicotinic acid hydrazide (isoniazid) as a model drug, while NAT2 alleles were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Among patients with SLE, NAT2*4/NAT2*6 and NAT2*5/NAT2*5 genotypes occurred most frequently, while NAT2*4/NAT2*6 and NAT2*5/NAT2*6 prevailed in the control group. The concordance of 96.8% was achieved between acetylation phenotype and NAT2 genotype in the group of SLE patients studied. CONCLUSION: Acetylation polymorphism appears not to be an important risk factor in SLE.

Frequency of common MDR1 gene variants in a Polish population.

P-glycoprotein (P-gp) is a transmembrane transporter playing an important role in drug efflux. There is growing evidence that P-gp activity may be related to haplotypes of MDR1 gene. In the current study, the frequencies of common functional polymorphisms in MDR1 gene (2677G > A,T and 3435C > T) were evaluated using PCR-RFLP and allele-specific amplification, in a group of 204 healthy individuals of Caucasian origin from Poland. It was found that the frequencies of the studied single nucleotide polymorphisms were similar to those reported for other Caucasian populations, and were as follows: 2677G-3435C--0.453, 2677G-3435T--0.143, 2677T-3435C--0.015, 2677T-3435T--0.370, 2677A-3435C--0.008, 2677A-3435T--0.011. The results of our study may give the basis for predicting pharmacokinetic and pharmacodynamic effects of many commonly used drugs in the Polish population.

MDR1 gene polymorphism in allogeenic kidney transplant patients with tremor.

P-glycoprotein (P-gp), an ATP-dependent efflux pump, is a membrane protein encoded by MDR1 gene, which demonstrates functional polymorphism. It is present in endothelial cells of the blood-brain barrier. P-gp pays a role in transmembrane transport of various xenobiotics, thus limiting their accumulation in the central nervous system. Cyclosporine A which is used as an immunosuppressive drug in patients with allogenic kidney grafts is a substrate for P-gp. Cyclosporine A may cause neurotoxic adverse effects, among them tremor. It was assumed that polymorphism of MDR1 gene which is associated with change in P-gp activity plays a role in induction of tremor in some patients with allogenic kidney graft treated with cyclosporine A. A total of 118 unrelated postransplant kidney patients were enrolled into the study. The tremor group included 23 cases and 95 randomly selected posttransplant individuals with no signs of tremor served as controls. No statistically significant correlation between MDR1 gene polymorphism C3435T and tremor was found. The tremor group and the control group were characterized by similar distribution of MDR1 genotypes, i.e. 3435CC, 3435CT, 3435TT.

Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients.

OBJECTIVE: The P-glycoprotein, a product of MDR1 (multiple drug resistance 1) gene, is a membrane efflux pump localized in epithelial cells in the small and large intestine, a part of the gastrointestinal barrier that protects cells against xenobiotics from our diet, bacterial toxins, drugs and other biologically active compounds, possibly carcinogens. In the present study, an association of MDR1 gene polymorphism and the occurrence of colon cancer were evaluated. METHODS: The study population consisted of 184 unrelated sporadic colon cancer patients and 188 healthy unrelated controls. Colon cancer patients were also subdivided into two subgroups, i.e., diagnosed before and after 50 years of age, and compared with age-stratified controls. The C3435T MDR1 gene polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The distribution of wild-type and mutated genotypes was similar in the colon cancer patients and in the healthy controls. However, when patients diagnosed before 50 years of age were compared with the healthy population, carriers of MDR1 3435TT genotype or 3435T allele were at 2.7-fold (P<0.05) and 1.7-fold (P<0.05) higher risk of the disease development, respectively. CONCLUSIONS: Genetic testing for C3435T MDR1 gene polymorphism may be a suitable test to evaluate the risk for colon cancer in patients under 50 years of age.

[The influence of IL-6 polymorphism on efficacy of treatment of rheumatoid arthritis patients with methotrexate and prednisone]. / Wplyw polimorfizmu interleukiny-6 na skutecznosc leczenia chorych na reumatoidalne zapalenie stawów metotreksatem i prednizonem.

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The therapy of RA is associated with application of the drugs modulating the immune response via inhibiting the cytokine production. The common drugs used in RA therapy are methotrexate and prednisone. Recent investigations showed the importance of genetically determined differences in cytokine production in RA activity and therapy. The aim of the present study was to examine the influence of - 174 interleukin-6 (IL-6) promoter polymorphism on the efficacy of treatment of RA patients with methotrexate and prednisone. Polymerase chain reaction amplification was used for analysis of the polymorphism at IL-6 gene. Seventy patients with RA diagnosed according to the criteria of the American College of Rheumatology were investigated. The patients were divided into two subgroups. The first subgroup included patients who have obtained remission for at least 6 months after therapy with methotrexate and glucocorticosteroids. The second subgroup included patients with active disease despite at least 6 months of therapy with methotrexate and glucocorticosteroids. It has been shown that the incidence of remission after therapy with methotrexate and glucocorticosteroids was significantly lower in patients with GG genotype as compared with GC and CC genotypes p< 0.05. We suggest that -174 IL-6 promoter polymorphism may be a genetic risk factor determining the effectiveness of RA treatement with methotrexate and glucocorticosteroids.