The use of Ctrough for the therapeutic drug monitoring of olaparib in patients with ovarian cancer.

OBJECTIVE: Olaparib is the poly-[Adenosine diphosphate ribose (ADP-ribose)] polymerase inhibitor (PARPI) used in maintenance therapy of patients with platinum-sensitive ovarian cancer with mutations in breast cancer genes 1/2 (BRCA1/2). Oncologists still do not have recommendations of treatment depending on efficient plasma concentrations of the PARP inhibitor. The aim of the study was the assessment of plasma trough concentrations of olaparib at steady state (Ctrough) in ovarian cancer patients. The severity of olaparib adverse effects (AEs) was noted. PATIENTS AND METHODS: The retrospective study involved 33 patients [mean standard deviation (SD)]; age 57.0 (8.4) years; weight 68.7 (13.7) kg; and body mass index (BMI) 26.4 (4.9) kg/m2, with ovarian cancer treated with olaparib (tablets in dose 300 mg/12 h, 250 mg/12 h, 200 mg/12 h or capsules 400 mg/12 h, 200 mg/12 h, 100 mg/12 h). Plasma drug levels were measured by HPLC-UV method (λ = 254 nm; Symmetry C8 column; gradient flow). The severity of olaparib AEs was assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale. Drug interactions were analyzed. RESULTS: In total, 130 measurements (n) of Ctrough were determined in 33 patients (median sample frequency per patient was 4). The olaparib Ctrough in patients with AEs was 87.840-7,213.262 ng/mL [coefficient of variation (CV) = 91%], in patients without AEs 48.021-7,073.350 ng/mL (CV = 88%). AEs were the following: fatigue (modest, n = 4, severe, n = 2), anemia (grade G1 n = 66, G2 n = 6, G3 n = 3), neutropenia (grade G1 n = 15, G2 n = 4), prediabetes (n = 1). There was a correlation between Ctrough and olaparib-induced fatigue (p = 0.0015). The lower values of dose-adjusted olaparib concentrations (p = 0.0121) and dose/kg-adjusted olaparib concentrations (p = 0.0389) were correlated with higher grade of neutropenia. CONCLUSIONS: There was a correlation between Ctrough, expressed as ng/ml, ng/ml/mg or ng/ml/mg/kg, and fatigue degree, but not anemia. Patients with neutropenia had statistically significant lower plasma concentrations of olaparib.

Ketoprofen and tramadol pharmacokinetics in patients with chronic pancreatitis.

OBJECTIVE: Chronic pancreatitis (CP) is a disease leading to irreversible pancreas dysfunction. One of the main symptoms is pain. Many patients require pharmacological therapy which should be started with paracetamol or, in selected groups of patients, ketoprofen. If the effect of ketoprofen is irrelevant, patients receive tramadol. The aim of this study is the evaluation of ketoprofen and tramadol pharmacokinetics (PK) in CP patients. PATIENTS AND METHODS: 36 patients were divided into two groups: I - receiving ketoprofen (n=18; mean [SD] age, 48.61 [13.32] years; weight, 73.28 [20.48] kg), II - receiving tramadol (n=18; mean [SD] age, 46.78 [10.28] years; weight, 74.22 [14.04] kg, and BMI (Body Mass Index), 24.61 [4.51] kg/m2). The plasma concentrations of ketoprofen and tramadol with its active metabolite M1 (0-desmethyltramadol) were measured with the validated high-performance liquid chromatography method. RESULTS: The main PK parameters for ketoprofen were as follows: Cmax (maximum plasma concentration), 3.41 [2.32] mg/L; AUC0-inf (area under the plasma concentration-time curve from time zero to infinity), 10.45 [5.57] mg⋅h/L; tmax (time to first occurrence of Cmax), 1.94 [1.25] h; Cl (clearance), 0.199 [0.165] L/kg·h, and Vd/kg (volume of distribution per kilogram of body weight), 0.71 [0.58] L/kg. The main PK parameters for TRM and M1 were as follows: Cmax, 226.4 [80.5] and 55.6 [23] ng/mL; AUC0-inf, 1903.3 [874.8] and 790.4 [512.4] ng⋅h/mL; tmax, 1.78 [0.73] and 2.67 [1.19] h, respectively. CONCLUSIONS: Chronic pancreatitis led to a decrease in the total amount of absorbed ketoprofen. Consequently, the analgesic effect of the drug may be weaker. Cmax of tramadol for most CP patients was within the therapeutic range associated with its analgesic activity. M1/TRM ratios for Cmax and AUC were unchanged.

The Importance of New Generation Sequencing (NGS) HLA Typing in Renal Transplantation-Preliminary Report.

INTRODUCTION: Thanks to new generation sequencing (NGS) and expansion of HLA typing with additional loci, it will be possible to increase the effectiveness of graft survival and to avoid complications related to the immune system. New pharmacogenetic factors are still being researched to develop better immunosuppressive treatment. MATERIAL AND METHODS: The incidence of polymorphic HLA loci variants was established, based on a high-resolution NGS method in kidney graft recipients. Furthermore, haplotypic analysis between examined loci was conducted to type additional loci that may influence the transplantation result. A total of 120 kidney recipients were enrolled in the study. A commercial DNA extraction kit in Tubes (QIAamp DNA Blood Mini Kit Qiagen, Germany) was used to isolate DNA from the blood. Sequencing library preparation was done with TruSight HLA set. The Conexio computer program was used to analyse the results of HLA typing. RESULTS: The patients with alleles A*02:01:01, B*44:02:01, C*03:03:01, C*01:02:01, C*05:01:01, C*07:02:01, DQB1*03:03:02, DQB1*06:04:01, or with haplotypic variation A*25:01:01-B*18:01:01- C*15:01:01 were taking the highest doses of cyclosporine (CsA), in contrast to patients with allele B*18:01:01, DQB1*06:02:01, DQB1*02:02:01, or haplotypic variation A*02:01:01- B*44:02:01-C*01:01:01, who were taking the lowest doses. The highest dose of tacrolimus (TAC) was administered to patients with alleles A*68:01:02, A*29:01:01, B*07:02:01, B*35:02:01, B*38:01:01, DRB1*12:01:01, DQB1*05:03:01, or haplotypic variations A*02:01:01-B*57:01:01-C*07:01:01, A*03:01:01-B*07:02:01-C*13:01:01, A*29:02:01-B*44:03:01- C*07:01:01, and A*01:01:01-B*08:01:01-C*03:01:01. Additionally, it was established that HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DPA1, and HLA-DQA1 show very slight polymorphism, which suggests that there is no need for their typing for transplantation purposes. Moreover, loci HLA-C, HLA-DQB1, and HLA-DPB1, which are not routinely examined in recipient-donor matching, show genetic variability that may increase the risk of transplant rejection or shortened graft life. CONCLUSIONS: Expanding the qualification procedure to include allele genotyping could allow clinicians to establish immunosuppressive treatment schemes that would be optimally suited for recipients' phenotype.

Duplicate use of angiotesin-converting enzyme (ACE) inhibitors in a community-dwelling elderly population in Poland.

In this paper the data on the duplicate use of ACE inhibitors among a community-dwelling elderly population are presented. Using a questionnaire, 1000 subjects were interviewed concerning the use of drugs, 654 females, mean+/-SD age: 72.6+/-6.5 years. They were divided into two groups: Group A (5%) taking at least two ACE inhibitors (n=50) and Group B: those who used either a single ACE inhibitor or no ACE inhibitor (n=950). In Group A, 49 individuals were taking two different ACE inhibitors concomitantly and one was using three. The most commonly used ACE inhibitor was enalapril (29 of 50 subjects). Subjects in Group A consumed significantly more drugs, both of prescription (Rx) and nonprescription (OTC), compared to those in Group B (total means: 8.4+/-2.8 vs. 6.7+/-3.2; p<0.01, Rx means: 6.3+/-2.5 vs. 5.2+/-2.8, p<0.05, OTC means: 2.0+/-1.6 vs. 1.6+/-1.5, p<0.05). Also, they were more likely to have consulted a cardiologist (17/50 vs. 201/950, p<0.05). The duplicate use of ACE inhibitors in 5% of a population of community-dwelling elderly patients seems to be caused by both poor doctor-doctor communication and polypharmacy. This phenomenon could possibly be dangerous especially when potential additive adverse effects are taken into account.

The influence of the tumor necrosis factor-alpa-308G>A polymorphism on the efficacy of immunosuppressive therapy in patients after kidney transplantation.

Cytokines play an important role in the immune response. The calcineurin inhibitors (cyclosporine CsA, tacrolimus TAC) widely used after renal transplantation to prevent allograft rejection are immunosuppressive drugs suppressing the production of cytokines. These drugs are characterized by interindividual variability and require monitoring their blood concentrations to predict their optimal dosage. Therefore, the aim of the study was to determine the correlation between therapeutic effects of immunosuppressants and the tumor necrosis factor-α (TNF-α)-308G>A polymorphism in renal transplant patients. A total of 412 patients receiving TAC and CsA were included in the study. Genotype frequencies were determined using the real-time PCR method. Patients with the GG genotype received higher doses of TAC as compared to carriers of the GA genotype (5.24 mg versus 3.35 mg) and had lower mean drug concentration in blood (5.86 ng/ml versus 6.92 ng/ml). Similar results were also obtained for CsA (GG: 185.33 mg versus GA: 153.30 mg, P < 0.05). The comparison of the TNF-α-308G>A polymorphism with the biochemical parameters did not reveal a potential risk for transplant rejection. These results indicate that the TNF-α-308G>A polymorphism may influence the dosage of immunosuppressive drugs in patients after transplantation as far as individualization of drug therapy is concerned.

The influence of the time-of-day administration of sunitinib on the penetration through the blood-brain and blood-aqueous humour barriers in rabbits.

OBJECTIVE: Sunitinib is a multiple tyrosine kinase inhibitor (TKI) that exerts anti-tumor and antiangiogenic activity. It is used for the treatment of metastatic gastrointestinal stromal tumours, renal cell carcinoma and pancreatic neuroendocrine tumours. A few studies confirm the anti-tumour activity of sunitinib in brain tumours and uveal melanoma, as well as its efficacy in the reduction of brain metastases of some primary cancers. Therefore, the penetration of sunitinib through the blood-brain barrier (BBB) and blood-aqueous humour barrier (BAB) is an issue of growing interest. The aim of the study was to investigate the influence of the time-of-day administration on the penetration of sunitinib into the cerebrospinal fluid (CSF) and aqueous humour (AH). MATERIALS AND METHODS: The rabbits were divided into two groups: I (control group)--receiving sunitinib at 8 a.m., and II--receiving sunitinib at 8 p.m. Sunitinib was administered p.o. at a single dose of 25 mg. The concentrations of sunitinib and its active metabolite (SU12662) in the plasma, CSF, AH were measured with the validated HPLC-UV method. RESULTS: The plasma AUC0-t for sunitinib in group I was 2051.8 ng × h/mL, whereas in group II it was 3069.3 ng × h/mL. The aqueous humour AUC0-t for sunitinib in thr groups were 43.2 and 76.3 ng × h/mL, respectively. The cerebrospinal AUC0-t for sunitinib in groups I and II were 55.5 and 66.3 ng × h/mL, respectively. CONCLUSIONS: After the evening administration (8 p.m.) the exposure to sunitinib in the rabbits' plasma, AH and CSF was higher than after the morning administration (8 a.m.), but the degree of sunitinib penetration through the BAB and BBB was very low (< 5%) and comparable in both groups.

The effect of bradykinin on the oxidative state of rats with acute hyperglycaemia.

Many clinical and experimental studies have established the beneficial effect of kinins in hypertension, heart failure and ischaemia-reperfusion syndrome, but little attention has been given to the role of kinins in hyperglycaemic conditions. The purpose of the present study was to determine the influence of bradykinin on the levels of glucose, insulin, malondialdehyde and hydrogen peroxide, as well as antioxidative enzyme activity in rats with streptozotocin (STZ)-induced acute hyperglycaemia. In STZ-induced hyperglycaemic rats the levels of glucose, hydrogen peroxide and malondialdehyde were increased by 256% (from 6.0+/-0.3 to 21.4+/-1.3 mmol/l, P<0.001), 33% (from 1.9+/-0.1 to 5.6+/-0.3 mmol H(2)O(2)/ml, P<0.001) and 19% (from 3.7+/-0.3 to 4.9+/-0.2 nmol/l, P<0.001) respectively. The activity of superoxide dismutase, catalase and glutathione peroxidase and the level of insulin were decreased by 46% (from 1367+/-73 to 737+/-59 U/g Hb, P<0.001), 36% (from 2.3+/-0.3 to 1.4+/-0.1 U Bergmayera/g Hb, P<0.001), 31% (from 236+/-19 to 163+/-24 U/g Hb, P<0.001) and 91% (from 47.5+/-1.7 to 2.4+/-0.5 mU/l, P<0.001) respectively in rats treated with streptozotocin. The administration of bradykinin caused the decrease in glucose, hydrogen peroxide and malondi-aldehyde levels by 38% (from 21.4+/-1.3 to 13.3+/-1.0 mmol/l, P<0.001), 37% (from 5.6+/-0.3 to 4.3+/-0.2 mmol H2O2/ml, P<0.001), 39% (from 4.9+/-0.2 to 3.0+/-0.2 nmol/l, P<0.001) respectively and the increase in insulin level and superoxide dismutase, catalase and glutathione peroxidase activity by 62% (from 2.4+/-0.5 to 4.0+/-0.4 mU/l, P<0.001), 23% (from 736.8+/-58.5 to 906.7+/-47.8 U/g Hb, P<0.001), 23% (from 1.4+/-0.1 to 1.9+/-0.1 U Bergmayera/g Hb, P<0.01) and 19% (from 163.1+/-23.6 to 202.3+/-11.7 U/g Hb, P<0.001) respectively in rats with hyperglycaemia. Thus, bradykinin is able to reduce oxidative stress in hyperglycaemic conditions.

Biopharmaceutical availability of sulphadicramide from ocular ointments in vitro.

The effect of absorption promoters, i.e. sodium deoxycholate, lauryl ether polioxyethylene-9, and l-alpha-lysophosphatidylo choline, on the process of sulphadicramide dialysis through lipophilic synthetic membranes and animal cornea in vitro, was studied. Formulation of ophthalmic ointments containing sulphadicramide and the above promoters was proposed and biopharmaceutical evaluation of the ointments was performed.

Technology and biopharmaceutical availability of solid ocular inserts containing sulfadicramide and some promoters.

Technology for obtaining solid ocular inserts made of poly(vinyl alcohol), containing sulfadicramide and some sorption promoters, was worked out. The rate of drug release was studied by assuming the pseudo-first order kinetics to hold true. An isolated animal cornea was used to measure the coefficients of permeability and the efficiency of sulfadicramide penetration through these corneas.

Pharmaceutical availability of clobetasol-17-propionate from cream and ointment.

Kinetics of drug release from both compared preparations available as a cream and an ointment, was in vitro studied. A reversed-phase HPLC method was developed for the determination of clobetasol-17-propionate in lipophylic bases using clobetasol-17-butyrate as an internal standard. Analyses were performed using a C18 reversed-phase column with a mobile phase of methanol-water and ultraviolet detection at lambda=254 nm. The calibration curve was constructed for the concentration range 0.5-40.0 microg/ml. The method is simple, accurate and precise.

Technology and physico-chemical evaluation of solid ocular inserts containing sulfadicramide and hyaluronic acid.

Synthetic lipophilic membranes, containing sulfadicramide (SDC), disodium salt of hyaluronic acid and disodium salt of taurolithocholic acid were prepared as described (Fürst et al.). Rate constants of SDC release from the above membranes and its apparent permeability coefficients through the comea isolated from the pig's eyes were determined.

[In vitro diffusion of 5-fluorourcil and tegafur through excized pig cornea]. / Etudes in vitro de la diffusion du 5-fluorouracil et du tégafur à travers la cornée oculaire de porc.

Permeability kinetics of 5-fluorouracil (5-FU), tegafur (TGF) and ftorafur (FT) through synthetic, lipophilic membranes and the pig excised cornea were studied. During the dialysis process, the drugs were dissolved in Ringer's solutions of either pH 6.89 or 7.98 and the drug concentrations were measured vs time by UV spectrophotometry at 37 degrees C. The diffusion processes of 5-FU, TGF and FT through the synthetic membranes were pH dependent and could be interpreted according to pseudo-first-order kinetics. However, the drug diffusion through the pig excised cornea was a zero-order process. The permeability rate of FT (TGF) across the pig cornea was greater if compared to that of 5-FU, whose partition coefficient (ko/w) was higher than those of the former drugs.

The influence of the time-of-day administration of the drug on the pharmacokinetics of sunitinib in rabbits.

OBJECTIVES: At present it is known that the adjustment of the anticancer therapy to the circadian rhythms in tissues reduces the toxicity of the treatment. Chronotherapy also increases the efficacy of the anticancer treatment, which has been proved for many drugs. Sunitinib is a tyrosine kinase inhibitor, which is broadly used for the treatment of numerous cancers. The aim of the study was a comparison of the concentrations and pharmacokinetics of sunitinib after a single administration to rabbits at 08:00 (control group) and 20:00. Additionally, the effect of sunitinib on glucose levels was investigated. MATERIALS AND METHODS: The research was carried out on two groups of rabbits: I08:00, a group with the drug administered at 08:00 (n=8) and II20:00, a group with the drug administered at 20:00 (n=8). The rabbits were treated with sunitinib at an oral dose of 25 mg. Plasma concentrations of sunitinib and its metabolite (SU12662) were measured with a validated HPLC method with UV detection. RESULTS: The comparison of the sunitinib Cmax and AUC0-t in the group with sunitinib administered at 20:00 with the control group gave the ratios of 2.20 (90% confidence interval (CI) (2.17; 2.22) and 1.64 (1.61; 1.68), respectively. Statistically significant differences between the groups under analysis were revealed for Cmax (p < 0.0001), AUC0-t (p = 0.0079), AUC0-∞ (p = 0.0149), and tmax (p = 0.0085). The mean glycemia drop was higher in group I08:00. than in group II20:00 (22.7% vs. 14.3%; p = 0.0622). The glycemia values returned to the initial values in 24 h after the administration of the drug in both groups. CONCLUSIONS: The research proved a significant influence of the time-of-day administration on the pharmacokinetics of sunitinib.

The pharmacokinetics of oral oxycodone in patients after total gastric resection.

OBJECTIVE: Oxycodone is a semi-synthetic opioid with a stronger analgesic effect than morphine and codeine. The efficacy of this opioid in the treatment of postoperative pain has been proved in different groups of patients. The drug has a favourable adverse reaction profile, which encourages doctors and patients to use it more and more widely. The drug is also used in the patients who underwent an abdominal surgery, e.g. stomach resection. Gastrectomy leads to pathophysiological changes within the gastrointestinal tract, which may cause changes in the drug absorption. In consequence this leads to a change in the pharmacokinetics and effect of the drug. The aim of the research was an analysis of the pharmacokinetics of oxycodone from prolonged release tablet in patients after total gastrectomy. PATIENTS AND METHODS: The research was carried out on patients after gastrectomy with Roux-en-Y reconstruction. The patients (n=24; mean [SD] age, 67.6 [9.8] years; weight, 69.1 [13.6] kg; and BMI, 25.2 [4.0] kg/m(2)) received oxycodone in a prolonged release tablet in a single orally administered dose of 10 mg. Blood samples were collected within 12 h after the drug administration. The plasma concentrations of oxycodone and noroxycodone were measured with validated high-pressure liquid chromatography coupled with triple tandem mass spectrometery method. RESULTS: The main pharmacokinetic parameters for oxycodone in men (n = 14) and women (n = 10) were as follows: Cmax, 14.40 (3.76) and 11.54 (6.98) ng/ml (p = 0.2066); AUC0-∞, 157.87 (56.89) and 106.44 (61.31) ng´h/ml (p = 0.0460); tmax, 2.18 (0.58) and 2.15 (0.58) h (p = 0.8008), respectively. CONCLUSIONS: Total gastrectomy did not affect the pharmacokinetics of oxycodone administered in prolonged release tablets, but the exposure to the drug was significantly lower in women.

Pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400 mg.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400 mg. MATERIAL/METHODS: Plasma concentrations were measured in 20 critically ill patients (mean [SD]; age, 55.5 [16.5] years; weight, 80.3 [16.9] kg; and creatinine clearance, 110.0 [71.5] mL/min). Four blood samples were drawn at the following time points 0, 0.5, 6 , 8 hours after infusion. Ciprofloxacin concentrations were determined by high-performance liquid chromatography. RESULTS: In the cases where ciprofloxacin was applied in targeted antibiotic therapy the minimum inhibitory concentrations (MIC) were ≤0.5 mg/l. The maximum and minimum plasma concentrations of ciprofloxacin were 1.74 (0.58-7.90) and 0.45 (0.16-2.96) mg/l, respectively. The main pharmacokinetic parameters for ciprofloxacin in the analyzed patients were as follows: k(el), 0.21 h-1; t(1/2kel), 3.37 h; AUC(0-inf), 10.10 mg×h/l; AUMC(0-last), 15.36 mg×h(2)/l; MRT, 1.71 h; V(d), 214.8 l; Cl, 39.70 l/h. Considering the maximum value of MIC (0.5 mg/l) only 30% and 25% of analyzed patients had desired values of the PK/PD indexes AUIC>125 and C(max) /MIC>10, respectively. CONCLUSIONS: The target plasma concentrations after the first dose of ciprofloxacin were reached only in a few critically ill patients. Considerable inter-subject variability for PK/PD parameters in ICU patients requires systematic monitoring.

Dielectric studies of the paracetamol-lenticular tissue interactions.

This paper reports on the effect of paracetamol on the dielectric behavior of the rabbit lens. Measurements were performed over the frequency range of 100 Hz-100 kHz in air and at the temperature of 35°C. The frequency dependencies of the relative permittivity and dielectric loss for the control and paracetamol-control lenses are described in terms of a power-low, Debye and Cole-Cole relations. The effect of paracetamol on the dielectric properties of the lens is visible in the lower values of the relative permittivity than those for the control sample at the same frequency. In addition, the relaxations around 18 and 46 kHz for the paracetamol-control lens are shifted to lower frequencies compared with the control lens. The results of this work indicate that the present method is useful in detection of the lens toxicity elicited by overdoses of paracetamol in animal.

Drug consumption among Polish centenarians.

The aim of the study was to describe the quantitative and qualitative aspects of pharmacotherapy of Polish centenarians. The studied group consisted of 92 centenarians (mean age: 101.7±1.2 years, 77 females, mean age: 101.5±1.2; 15 males mean age: 102.2±1.2). Among the studied subjects, 18 individuals (19.6% of all subjects) did not use any drugs in his or her daily regimen. The mean number of drugs per person was 2.5±2.5 drugs (prescription drugs: 1.9±2.2 and non-prescription drugs: 0.5±0.8). Fifty-six centenarians (60.9% of all studied subjects) took concomitantly 0-3 drugs daily while 36 (39.1%) took more than 3 drugs daily. Within this group, 30 centenarians (32.6%) took 5 or more drugs concomitantly every day. The most commonly used groups of drugs were: gastrointestinal drugs (55 centenarians, 74.3% of all drug consumed), cardiovascular drugs (51 centenarians, 68.9%) and central nervous system drugs (N) (38 centenarians, 51.4%). In the studied group, 6 persons (8.1% of all drug consumers) were taking one potentially inappropriate drug based on the Beers criteria. To conclude, the mean number of drugs, the prevalence of polypharmacy, and the tendency for potential inappropriateness of treatment are lower among Polish centenarians comparing to the common elderly.

The effect of standardized Echinacea purpurea extract on rat cytochrome P450 expression level.

It is claimed that application of botanical supplements or herbal medicinal products with synthetic drugs that are cytochrome P450 enzymes substrates may induce significant herb-drug interactions and may alter pharmacotherapy. Echinacea preparations are one of the best selling products in the Europe and their medicinal use is still increasing but data about interactions of Echinacea extract with CYP enzymes are limited. In this study, we have investigated potential influence of standardized Echinacea purpurea extract containing 3.7% polyphenolic compounds on the mRNA expression level of major CYP450 enzymes using animal model. Total RNA was isolated from the rat liver tissue according to the manufacturer's protocol. Complementary DNA was synthesized from a mature mRNA template using reverse transcription. The level of mRNA expression in liver was analyzed by real-time quantitative PCR using specific target primers for CYP450 genes. In this study, it was demonstrated a significant increase of rat CYP2D1 and CYP1A1 expression level by 40% (p = 0.007) and 80% (p = 0.01), respectively. A weak inductory effect of the extract was observed for CYP1A2 by 16% (p > 0.05) compared with the control group. The levels of rat CYP3A1 and CYP3A2 mRNA were reduced by 41% (p < 0.05) and 25% (p = 0.001), respectively. A weak inhibitory effect was observed for CYP2D2 by 15% (p = 0.008) and CYP2C6 by 18% (p = 0.004) after long application of the Echinacea ethanolic extract. CYP2D2 and CYP2C6 activities were also inhibited by extract but in a lesser degree than CYP3A1 activity. Moreover, very little or no inhibition was noted for CYP2E1 both after 3 and 10 days of treatment. Our in vivo data indicate that the Echinacea ethanolic extract can potently inhibit the expression of CYP3A1/2 and can also induce of CYP1A1, CYP2D1. These findings suggest that Echinacea extract may influence the P450-mediated metabolism of different drugs and may initiate chemical carcinogenesis by activation of some compounds to their carcinogenic metabolites.