CYP2C19 polymorphism in relation to the pharmacotherapy optimization of commonly used drugs.

Purpose: The CYP2C19 isoenzyme plays an important role in the efficacy and safe use of many drugs. The aim of this review is to demonstrate how CYP2C19 mutations influence everyday patient treatment, leading to adverse drug reactions or therapy failure in many common diseases. Methods: A PubMed literature search was performed on clinical publications evaluating the impact of CYP2C19 on pharmacotherapy outcome. Main fields of medicine with strong outcome dependency on the CYP2C19 genotype were selected. We also focused on clinical recommendations for the use of drugs referring to CYP2C19 polymorphism. Results: The fields of medicine where clinical outcome particularly depends on CYP2C19 polymorphism are gastroenterology, cardiology, psychiatry, mycology and oncology. CYP2C19 is involved in proton pump inhibitors metabolism, thus it can influence reflux therapy, ulcer prevention and Helicobacter pylori eradication treatment. The CYP2C19 enzyme plays also a vital role in the two bioactivation steps of clopidogrel leading to lower (CYP2C19*17 carriers) or higher (CYP2C19*2 carriers) risk of major adverse cardiovascular events. It affects the antidepressant treatment and methadone replacement therapy as well as voriconazole prophylaxis. The presence of a *2 allele is associated with longer relapse-free time or better survival, and the *17 allele with more favorable outcomes in breast cancer patients treated with tamoxifen. Conclusions: Knowledge of the CYP2C19 polymorphism could positively affect individual treatment and lead to better patient outcomes in many cases. The introduction of pharmacogenetic testing into medical practice would be a good way to minimize negative outcomes of therapy, and to reduce unnecessary medical costs.

The impact of CYP3A5 on the metabolism of cyclosporine A and tacrolimus in the evaluation of efficiency and safety of immunosuppressive treatment in patients after kidney transplantation.

The aim of the study was to determine the impact of CYP3A5 mutation on the serum levels of immunosuppressive drugs (tacrolimus and cyclosporine A), and on the occurrence of acute rejection episodes among patients after kidney transplantation. A limited number of such research in Polish patients was also an important factor encouraging to perform the study. Fifty-two persons were recruited. The tested patients underwent kidney transplantation and were treated either with cyclosporine A (17 persons) or with tacrolimus (35 persons). The group included 21 women and 31 men. DNA was isolated from whole blood and a modified Van Schaik et al. (2002) PCR-RFLP method was used for genotyping. The serum levels were controlled at the 7th, 14th, 30th, 90th, 180th and 360th day after transplantation. The CYP3A5 genotype had no impact on the concentrations of cyclosporine A and tacrolimus at any investigated time point. No correlation between the rate of acute rejection episodes and different genotypes of the CYP3A5 isoenzyme could be proven.

Monitoring methotrexate therapy in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. MATERIAL AND METHODS: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. RESULTS: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-beta-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. CONCLUSION: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug.

Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab.

OBJECTIVE: This study was aimed at monitoring the early and late effects of infliximab on renal proximal function in RA patients treated with methotrexate. N-acetyl-3-D-glucosaminidase (NAG) activity in urine served as an indicator of proximal tubular damage METHODS: NAG activity was estimated in 21 patients during the course of treatment with infliximab and methotrexate. In every patient NAG-enzymuria was estimated directly before and 60 min after infliximab infusions and 62 weeks after starting the therapy. RESULTS: The total of mean NAG activities observed before each infusion of infliximab was significantly lower (p < 0.02) than NAG-enzymuria before the start of infliximab treatment (7.4 UI/g vs 11.8 UI/g). The proportion of patients in whom NAG activity rose by more than 50% during treatment ranged from 5.3% to 25%. Administration of infliximab did not significantly change the mean serum creatinine levels or creatinine clearance. No significant differences were observed in the mean values of NAG values before and 60 min after infliximab infusion. Patients who demonstrated elevated NAG activities during the course of the whole treatment demonstrated significantly more pronounced NAG enzymuria before treatment and one hour after the first infusion (p < 0.0005), as well as higher RA activity (p < 0.05). There was no observed influence of NSAIDs or prednisone on the frequency of elevated NAG activities. Raised creatinine concentrations (> 1.3 mg/dL) were noted before and during the course of infliximab treatment in 3 patients. In 16 patients abdominal fat aspiration biopsy was performed and in 3 the presence of amyloid deposits was demonstrated. In these patients NAG activity exceeded twice the upper normal limit. CONCLUSION: The introduction of infliximab during methotrexate therapy demonstrated no early or delayed nephrotoxicity of the drug in patients with rheumatoid arthritis.

Metabolic functions of the liver during chemotherapy in children with acute lymphoblastic leukemia.

OBJECTIVE: The purpose of the present work was estimation of liver function using the phenazone test and commonly used biochemical tests in children with acute lymphoblastic leukemia (ALL) during anticancer treatment. METHODS: Observations were carried out in the same 21 patients with ALL before the beginning of chemotherapy, after Protocol I and after Protocol M of the antileukemic treatment carried out according to the program BFM 86. RESULTS: The applied chemotherapy inhibited phenazone elimination. Both phenazone half-life and metabolic clearance rate were significantly different in patients after treatment with anticancer drugs, especially with high-dose of methotrexate (MTX), from those in patients before the beginning of chemotherapy (p < 0.001). Moreover, after MTX administration transaminases activity and serum bilirubin concentration were significantly higher than before treatment (p < 0.05). CONCLUSION: Our results showed that in children with acute lymphoblastic leukemia, anticancer chemotherapy decreased liver metabolic capacity. Particularly, high-dose methotrexate treatment altered the elimination of phenazone by inhibiting the activity of hepatic mixed function oxidase system. This change may lead to an increase in toxicity of active drugs which are metabolized by this enzyme system. In addition, altered activity of liver metabolic function can impair transformation of prodrugs to active forms. It should be considered in selection of individual drug dosages. The objective estimation of the type and degree of liver dysfunction can only be achieved by the combination of a quantitative phenazone dynamic test and static biochemical tests.

[Monitoring of renal function in epileptic children and teenagers treated with valproic acid or carbamazepine in concomitant therapy with tiagabine]. / Monitorowanie czynnosci nerek u dzieci i mlodziezy chorych na padaczke leczonych kwasem walproinowym lub karbamazepina w terapii skojarzonej z tiagabina.

The aim of the study was the evaluation of the influence of 4-month concomitant tiagabine (TGB) and valproic acid (VPA) or carbamazepine (CBZ) therapy on renal function of epileptic children and teenagers. Initial parameter values, indicated on renal disfunction, were compared with these obtained after VPA and TGB or CBZ and TGB therapy and with values in healthy children and teenagers. Investigation group was composed of 22 children and teenagers with drug-resistant focal epilepsy. We observed that in the time of concomitant VPA and TGB therapy increased the NAG/g creatinine activity index. In spite the fact of statistical significance of these changes, they were not outside the normal range. beta 2-microglobulin concentrations in urine of epileptic children treated with VPA in monotherapy before concomitant therapy with TGB were higher than in control group. That difference was statistically significant. Addition of TGB to the therapy normalized this parameter. During concomitant VPA and TGB or CBZ and TGB therapy we didn't observe statistically significant changes of parameters indicating on glomerular disfunction. In the VPA therapy before concomitant treatment with tiagabine the disfunction of tubules and glomerules was observed. On the other side in the concomitant VPA and TGB therapy the disfunction of tubules and glomerules didn't occurred. We can conclude that concomitant therapy VPA or CBZ with tiagabine don't affect the renal function in clinical significant manner. Therapy with VPA could leads to minimal disfunction of tubules what is represented by increasing of beta 2-microglobulin level in urine.

[Adverse reactions of coumarin derivative interactions]. / Niepozadane nastepstwa interakcji pochodnych kumaryny.

Many drugs interact with warfarin and other oral anticoagulants. Some of them reduce the activity of the anticoagulants and intensify of thrombosis symptoms. Others increase the activity and can cause bleeding if the dosage of the anticoagulant is not reduced appropriately. Both situations are clinically serious and may be fatal. Details of these interactions are given in this article.

Phenazone as a marker of liver-metabolic function in patients with acute leukemia.

OBJECTIVE: The aim of this work was to study the influence of neoplastic disease, especially acute myeloblastic leukemia (AML), and its chemotherapy on the activity of hepatic microsomal enzymes by using phenazone, as a marker of oxidative drug metabolizing activity. METHODS: The observations were carried out in 21 patients with AML and in 53 healthy volunteers. The influence of disease on phenazone kinetics was studied before chemotherapy and the effect of anticancer drugs administration after the first cycle of chemotherapy. RESULTS: The mean phenazone half-life time was significantly shorter in patients with AML (8.79 (3.01) h) than in control group (11.08 (3.61) h) (p < 0.012). Treatment with anticancer drugs, especially with epirubicine, inhibited phenazone elimination. The mean phenazone half-life time was significantly longer (18.08 (8.80) h) and the mean metabolic clearance rate was significantly smaller (33.92 (15.40) ml/min) after chemotherapy in comparison with the initial value, before treatment (10.22 (2.90) h), (p < 0.01) (50.33 (20.29) ml/min) (p < 0.008). CONCLUSION: Our results lead to the conclusion that phenazone is an important index of hepatic metabolic capacity in patients with acute myeloblastic leukemia. The evaluation of its kinetics allowed to early recognition of the presence and the degree of drug oxidizing modification. Acceleration of phenazone elimination before treatment and its inhibition after chemotherapy, particulary epirubicine, may suggest that in patients with AML elimination of the other drugs metabolized by the pathway similar to phenazone also may be changed. It should be considered in individualization of their dosage regimen.

[The significance of beta 2-microglobulin in diagnosis and therapy]. / Znaczenie beta 2-mikroglobuliny w diagnostyce i terapii.

This article describes the significance of beta 2-microglobulin (beta 2m) determination both in urine and serum for the estimation of proximal renal tubular function and glomerular filtration rate. The usefulness of beta 2m in therapy, cancer diagnosing, epidemiologic investigations of industrial exposure to cadmium, lead, mercury and in evaluating etiologic factors of environmental nephropathies was also discussed.

[Biotransformation of phenazone and sulfadimidine as markers of liver metabolism of drug and xenobiotic oxidation and acetylation in women with breast cancer]. / Biotransformacja fenazou i sulfadimidyny jako wskazników watrobowego metabolizmu leków i ksenobiotyków droga utleniania i acetylacji u kobiet chorych na raka sutka.

The aim of our study was to determine phenazone pharmacokinetics as an index of hepatic microsomal enzymes activity and acetylation phenotype in women with breast cancer. Phenazone test was made in 41 women with breast cancer and in 25 healthy women as a control group. Acetylation phenotype was measured in 40 women with breast cancer and in 25 healthy women as a control group. The plasma concentration of phenazone was estimated by the spectrophotometric method of Brodie and associates. Acetylation phenotype was determined by the Bratton-Marshall method in Varley's modification. The mean phenazone half-life time (t0,5), shortened significantly and the mean elimination rate constant (K) increased in women compared with a group of healthy persons. Mean clearance rate was increased in women with breast cancer too, compared with a group of healthy women. Acceleration of phenazone elimination may suggest that in patients with breast cancer elimination of the other drugs metabolized by the pathway similar to phenazone also may be changed. This should be considered in selection of their dosage. We have observed the predominance of rapid acetylators in women with breast cancer comparing with healthy persons. This difference was not statistically significant. Our results of acetylation phenotype in women with breast cancer suggests that rapid acetylation may be a factor of susceptibility to breast cancer.

[Evaluation of phenazone oxidation and sulfadimidine acetylation in patients with hematologic neoplasms]. / Ocena procesów utleniania fenazonu i acetylacji sulfadimidyny u chorych na nowotwory krwi.

The aim of our study was to estimate of phenazone oxidation and sulfadimidine acetylation in patients with Hodgkins disease, non Hodgkins lymphoma and acute leukemia. We observed increase in liver microsomal enzyme activity and predominance of the rapid acetylator phenotype in these pathological states. It should be taken into account when dosing drugs which are metabolized as markers of the liver metabolic efficiency like phenazone and sulphadimidine. One can also expect these patients to have a genetic predisposition to the development of cancer disease.

[Comparison of the effectiveness of metoclopramide and dexamethasone in the prevention of cytostatic-induced vomiting]. / Porównanie skutecznosci metoklopramidu i deksametazonu w zapobieganiu wymiotom po cytostatykach.

Efficiency of anti-emetic properties of metoclopramide and dexamethasone was compared. Both drugs were administered to 22 patients with newly diagnosed untreated previously Hodgkin's disease during ABVD therapy. Number of vomiting episodes, nausea intensity and everyday patients' activity on the day of cytostatics administration were evaluated. Metoclopramide prevented vomiting in 55% of patients while dexamethasone in 65%. This difference was statistically insignificant. Patients' everyday activity was statistically significantly more frequently normal in patients receiving dexamethasone in comparison with placebo and decreased in patients receiving metoclopramide. Therefore, patients preferred dexamethasone.