Assessment of omeprazole and famotidine effects on the pharmacokinetics of tacrolimus in patients following kidney transplant-randomized controlled trial.

Tacrolimus is metabolized in the liver with the participation of the CYP3A4 and CYP3A5 enzymes. Proton pump inhibitors are used in kidney transplant patients to prevent duodenal and gastric ulcer disease due to glucocorticoids. Omeprazole, unlike famotidine, is a substrate and inhibitor of the enzymes CYP2C19, CYP3A4, CYP3A5. The aim of this study was to compare the impact of omeprazole and famotidine on the pharmacokinetics of tacrolimus. A randomized, non-blinded study involving 22 stabilized adult kidney transplant patients was conducted. Patients received the standard triple immunosuppression regimen and omeprazole 20 mg (n = 10) or famotidine 20 mg (n = 12). The study material consisted of blood samples in which tacrolimus concentrations were determined using the Chemiluminescent Microparticle Immuno Assay method. A single administration of omeprazole increased tacrolimus concentrations at 2 h (day 2) = 11.90 ± 1.59 ng/mL vs. 2 h (day 1 - no omeprazole administration) = 9.40 ± 0.79 ng/mL (p = 0.0443). AUC0-6 amounted to 63.07 ± 19.46 ng × h/mL (day 2) vs. 54.23 ± 10.48 ng × h/mL (day 1), (p = 0.0295). AUC2-6 amounted to 44.32 ± 11.51 ng × h/mL (day 2) vs. 38.68 ± 7.70 ng × h/mL (day 1), (p = 0.0130). Conversely, no significant changes in values of pharmacokinetic parameters were observed for famotidine. Omeprazole significantly increases blood exposure of tacrolimus. The administration of famotidine instead of omeprazole seems safer for patients following kidney transplantation. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05061303.

Bidirectional pharmacokinetic drug interactions between olaparib and metformin.

OBJECTIVE: Olaparib is a PARP (poly-ADP-ribose polymerase) inhibitor used for maintenance therapy in BRCA-mutated cancers. Metformin is a first-choice drug used in the treatment of type 2 diabetes. Both drugs are commonly co-administered to oncologic patients with add-on type 2 diabetes mellitus. Olaparib is metabolized by the CYP3A4 enzyme, which may be inhibited by metformin through the Pregnane X Receptor. In vitro studies have shown that olaparib inhibits the following metformin transporters: OCT1, MATE1, and MATE2K. The aim of the study was to assess the influence of 'the perpetrator drug' on the pharmacokinetic (PK) parameters of 'the victim drug' after a single dose. To evaluate the effect, the AUC0→∞ (area under the curve) ratio was determined (the ratio between AUC0→∞ in the presence of the perpetrator and AUC0→∞ without the presence of the perpetrator). METHODS: Male Wistar rats were assigned to three groups (eight animals in each group), which were orally administered: metformin and olaparib (IMET+OLA), vehiculum with metformin (IIMET), and vehiculum with olaparib (IIIOLA). Blood samples were collected after 24 h. HPLC was applied to measure the concentrations of olaparib and metformin. The PK parameters were calculated in a non-compartmental model. RESULTS: Metformin did not affect the olaparib PK parameters. The AUC0→∞ IMET+OLA/IIIOLA ratio was 0.99. Olaparib significantly increased the metformin Cmax (by 177.8%), AUC0→t (by 159.8%), and AUC0→∞ (by 74.1%). The AUC0→∞ IMET+OLA/IIMET ratio was 1.74. CONCLUSIONS: A single dose of metformin did not affect the PK parameters of olaparib, nor did it inhibit the olaparib metabolism, but olaparib significantly changed the metformin pharmacokinetics, which may be of clinical importance.

Göttingen pigs as a potential model for natalizumab pharmacokinetics, pharmacodynamics, and immunogenicity evaluation.

Natalizumab is a recombinant, humanized form of a monoclonal antibody that binds to CD49d. The presented study was conducted to explore the suitability of Göttingen pigs as a pharmacokinetic/pharmacodynamic model in the preclinical phase of biosimilar natalizumab development. The minipigs were treated with 1.286 or 3.0 mg of natalizumab (Tysabri®) per kg of body weight by a single 1-hour intravenous infusion. Six days before (baseline) and 30 days after administration of the single dose of natalizumab, blood samples were taken for analysis. No signs of local or general intolerance were observed. The pharmacokinetics plot shows a biphasic profile dependent on anti-drug antibody (ADA) levels. A dose-related increase in the CD49d saturation was observed immediately after the end of the infusion. The soluble vascular cell adhesion molecule (sVCAM) concentrations of the female animals were moderately decreased immediately after the end of infusion compared to the predose levels. The soluble mucosal addressin cell adhesion molecule (sMAdCAM) concentrations were slightly decreased compared to the predose levels starting immediately after the end of infusion and lasting for the next 30 days. All animals treated appeared to produce ADA. The concentrations of the ADA ranged from 15.8 to 16,748 ng/mL Göttingen pigs represent a suitable model for pharmacokinetic analysis and mechanism of action evaluation related to saturation of CD49d.

Effects of Bisphenol A and Bisphenol F on Porcine Uterus Contractility.

Introduction: Bisphenols, as endocrine disruptors, may cause a wide range of health problems in humans, but so far, not all of them have been confirmed in animals, including pigs. Since animals are also exposed to bisphenols, we hypothesised that these substances may have an effect on uterine contractility in pigs. Therefore, the aim of the study was to investigate the effect of the most-used bisphenol, bisphenol A (BPA), and a selected analogue, bisphenol F (BPF), on the contractile activity of the pig uterus. Material and Methods: The investigation utilised smooth muscles from immature pigs (n = 6), cyclic pigs on days 12-14 of the oestrous cycle (n = 6) or early pregnant pigs on days 12-16 of pregnancy (n = 6). Strips of the myometrium were exposed to BPA and BPF at concentrations of 10-13-10-1 M. Smooth muscle contractility was determined with equipment for measuring isometric contractions. Results: BPA caused a significant decrease in contraction amplitude, and frequency and in myometrial tension in all groups examined. BPF caused a decrease in the amplitude and frequency of contractions in all groups and in myometrial tension in the early pregnant group. Conclusion: The obtained results indicate that both BPA and BPF relaxed the porcine myometrium, but these changes, especially in the amplitude and frequency of contractions, were more evident after BPF treatment. The extent of relaxation is dependent on the physiological status of the animals.

4-Week toxicity study of biosimilar natalizumab in comparison to Tysabri® by repeated intravenous infusion to cynomolgus monkeys.

The objective of the study was to obtain information on the toxicity of biosimilar natalizumab (PB006) in comparison to the reference product Tysabri®. Cynomolgus monkeys (15 males and 15 females), three animals per sex and group were treated with either PB006 or the reference product Tysabri® at dose levels of 3 or 30 mg/kg body weight or placebo by intravenous infusion every other day for a period of 4 weeks. The study is also meant to facilitate ethics committee approval in specific countries for the planned confirmatory efficacy and safety study in patients. Based on study findings, it was concluded that there was no noteworthy difference between the animals treated with PB006 and the animals treated with Tysabri®. There were no noteworthy differences between PB006 and Tysabri® with respect to local tolerance, toxicity and pharmacokinetic profile in cynomolgus monkeys. In conclusion, obtained data are valid and suitable to support entry into clinical studies of PB006 in man.

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats.

A combination of the tyrosine kinase inhibitor-sorafenib-and the opioid analgesic-morphine-can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug-drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC0-t, and AUC0-∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0-t of its active metabolite-sorafenib N-oxide-was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0-t, and AUC0-∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

Ustekinumab pharmacokinetics after subcutaneous administration in swine model.

BACKGROUND: Due to multiple similarities in the structure and physiology of human and pig skin, the pig model is extremely useful for biological drug testing after subcutaneous administration. Knowledge of the differences between subcutaneous injection sites could have a significant impact on the absorption phase and pharmacokinetic profiles of biological drugs. OBJECTIVES: This study aimed to analyze the impact of administration site on pharmacokinetics and selected biochemical and hematological parameters after a single subcutaneous administration of ustekinumab in pigs. Drug concentrations in blood plasma were analyzed by enzyme-linked immunosorbent assay. Pharmacokinetic analyses were performed based on raw data using Phoenix WinNonlin 8.1 software and ThothPro v 4.1. METHODS: The study included 12 healthy, female, large white piglets. Each group received a single dose of ustekinumab given as a 1 mg/kg subcutaneous injection into the internal part of the inguinal fold or the external part of the inguinal fold. RESULTS: The differences in absorption rate between the internal and external parts of the inguinal fold were not significant. However, the time of maximal concentration, clearance, area under the curve calculated between zero and mean residence time and mean residence time between groups were substantially different (p > 0.05). The relative bioavailability after administration of ustekinumab into the external part of the inguinal fold was 40.36% lower than after administration of ustekinumab into the internal part of the inguinal fold. CONCLUSIONS: Healthy breeding pigs are a relevant model to study the pharmacokinetic profile of subcutaneously administered ustekinumab.

Quercetin affects uterine smooth muscle contractile activity in gilts.

Quercetin is a polyphenolic flavonoid occurring in leaves, stems, flowers and fruits of many plants. In traditional Chinese medicine, it is used as a natural therapeutic agent with a broad spectrum of activities (antioxidant, neuroprotective, anti-inflammatory, anticancer, antibacterial and antiviral). Moreover, quercetin affects function of the reproductive tract, however the knowledge of this activity is still fragmentary. Therefore, this study aimed to determine the influence of quercetin on the contractile activity of the porcine myometrium collected from immature (n = 6), cyclic (n = 6) and early pregnant (n = 6) gilts. Strips of the myometrium (comprising longitudinal and circular layer) were resected from the middle part of the uterine horns and the isometric contractions were recorded. After 60-90 min of preincubation, the strips were stimulated with quercetin in increasing (10-13-10-1 M) concentrations and the changes in the tension amplitude and frequency of contractions were measured. Quercetin decreased (P<0.01-0.001) the amplitude of contractions at concentrations 10-11-10-1 M and 10-10-10-1 M in cyclic and early pregnant groups, respectively. The frequency of contractions decreased in all groups but was the highest (at concentrations 10-11-10-1 M; P<0.05-0.001) in the cyclic group and the lowest (at concentrations 10-5-10-1 M; P<0.01) in the immature group. The tension decreased only in the cyclic group after quercetin administration in high concentrations (10-6-10-1 M; P<0.05-0.01). The results indicate that quercetin causes relaxation of the porcine uterine smooth muscle but this activity is strongly related to the physiological status of the gilts.

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model.

The loss of immune tolerance to fetal antigens may result in reproductive failure. The downregulated number and activity of T regulatory lymphocytes, which are critical for the establishment of immune tolerance to fetal antigens, during pregnancy may lead to miscarriage. The adoptive transfer of Tregs prevents fetal loss in abortion-prone mice. Recently, we demonstrated that the administration of tregitopes, which are short peptides found in human and mouse immunoglobulins (IgGs), decreased the incidence of abortions in female CBA/J mice mated with DBA/2J mice. Here, two non-IgG source peptides (SGS and LKD) that can potentially bind to the major histocompatibility complex II (MHC II) with high affinity and induce Treg expansion were designed in silico. The immune dysregulation-induced pregnancy failure mouse model was used to evaluate the effect of SGS and LKD on immune response and pregnancy outcome. The fetal death rate in the SGS-treated group was lower than that in the phosphate-buffered saline-treated group. SGS and LKD upregulated the splenic pool of Tregs and modulated the T-helper cell (Th1)/Th2-related cytokine response at the preimplantation stage. Additionally, SGS and LKD downregulated the expression of CD80 and MHC class II molecules in splenic CD11c+ antigen-presenting cells. Thus, SGS treatment can result in beneficial pregnancy outcomes. Additionally, SGS peptide-mediated immunomodulation can be a potential therapeutic strategy for immune dysregulation-induced pregnancy failure.

Selective Cytotoxicity of Complexes with N,N,N-Donor Dipodal Ligand in Tumor Cells.

The present article demonstrates selective cytotoxicity against cancer cells of the complexes [Co(LD)2]I2∙CH3OH (1), [CoLD(NCS)2] (2) and [VOLD(NCS)2]∙C6H5CH3 (3) containing the dipodal tridentate ligand LD = N,N-bis(3,5-dimethylpyrazol-1-ylmethyl)amine), formed in situ. All tested complexes expressed greater anticancer activities and were less toxic towards noncancerous cells than cisplatin. Cobalt complexes (1 and 2) combined high cytotoxicity with selectivity towards cancer cells and caused massive tumour cell death. The vanadium complex (3) induced apoptosis specifically in cancer cells and targeted proteins, controlling their invasive and metastatic properties. The presented experimental data and computational prediction of drug ability of coordination compounds may be helpful for designing novel and less toxic metal-based anticancer species with high specificities towards tumour cells.

Midazolam and hydroxymidazolam plasma concentrations can be monitored with selected biochemical and physiological parameters of palliative care patients.

RATIONALE & OBJECTIVE: Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFRCR) and the Modification of Diet in Renal Disease (eGFRMDRD) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (Mavg) and alfahydroxymidazolam (OH-Mavg) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy. STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS: The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among Mavg, BMI, eGFRMDRD, midazolam clearance (CL), OH-Mavg, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability. RESULTS: We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFRMDRD→CL and the (Bil + BMI × Ln(Cr))→Mavg-(OH-Mavg) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose. CONCLUSIONS: The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.

In vivo assessment of potential for UGT-inhibition-based drug-drug interaction between sorafenib and tapentadol.

Sorafenib (SR) is one of the most potent UGT (1A1, 1A9) inhibitors (in in vitro tests). The inhibition of UGT1A1 may cause hyperbilirubinaemia, whereas the inhibition of UGT1A9 and 1A1 may result in drug-drug interactions (DDIs). Tapentadol (TAP) is a synthetic µ-opioid agonist and is used to treat moderate to severe acute pain. Tapentadol is highly glucuronidated by the UGT1A9 and UGT2B7 isoenzymes. The aim of the study was to assess the DDI between SR and TAP. Wistar rats were divided into three groups, with eight animals in each. The rats were orally treated with SR (100 mg/kg) or TAP (4.64 mg/kg) or in combination with 100 mg/kg SOR and 4.64 TAP mg/kg. The concentrations of SR and sorafenib N-oxide, TAP and tapentadol glucuronide were respectively measured by means of high-performance liquid chromatography (HPLC) with ultraviolet detection and by means of ultra-performance liquid chromatography-tandem mass spectrometry. The co-administration of TAP with SR caused TAP maximum plasma concentration (Cmax) to increase 5.3-fold whereas its area under the plasma concentration-time curve (AUC0-∞) increased 1.5-fold. The tapentadol glucuronide Cmax increased 5.3-fold and whereas its AUC0-∞ increased 2.0-fold. The tapentadol glucuronide/TAP AUC0-∞ ratio increased 1.4-fold (p = 0.0118). TAP also increased SR Cmax 1.9-fold, whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide Cmax increased 1.9-fold whereas its AUC0-∞ increased 1.3-fold. The sorafenib N-oxide/SR AUC0-t ratio increased 1.4-fold (p = 0.0127). The results show that the co-administration of sorafenib and tapentadol increases the exposure to both drugs and changes their metabolism. In consequence, the pharmacological effect may be intensified, but the toxicity may increases, too.

In vivo assessment of the drug interaction between sorafenib and paracetamol in rats.

PURPOSE: Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. Neoplastic diseases are the cause of pain, which may occur regardless of the stage of the disease. Paracetamol is a non-opioid analgesic used alone or in combination with opioids for the treatment of cancer pain. Numerous studies have pointed out changes in the pharmacokinetic parameters of TKIs when co-administered with paracetamol. The aim of the study was to assess drug-drug interactions (DDIs) between sorafenib and paracetamol. METHODS: Rats were divided into three groups, each consisting of eight animals. The first group received sorafenib (IIS), the second group received sorafenib + paracetamol (IS+PA), whereas the third group received only paracetamol (IIIPA). A single dose of sorafenib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. The plasma concentrations of sorafenib and its metabolite-N-oxide as well as paracetamol and its glucuronide and sulphate metabolites were measured using validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. RESULTS: The co-administration of sorafenib and paracetamol increased the maximum concentration (Cmax) of paracetamol by 33% (p = 0.0372). In the IS+ PA group the Cmax of paracetamol glucuronide was reduced by 48% (p = < 0.0001), whereas the Cmax of paracetamol sulphate was higher by 153% (p = 0.0012) than in the IIIPA group. Paracetamol increased sorafenib and sorafenib N-oxide Cmax by 60% (p = 0.0068) and 83% (p = 0.0023), respectively. CONCLUSIONS: A greater knowledge of DDI between sorafenib and paracetamol may help adjust dose properly and avoid toxicity effects in individual patients.

The oxidation and hypoglycaemic effect of sorafenib in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetes reduces the activity of CYP3A4 and may increase the exposure for the drugs metabolized by the isoenzyme. Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI), used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. The TKI undergoes CYP3A4-dependent oxidative transformation, which may be influenced by hyperglycaemia. The aim of the study was to compare the oxidation for sorafenib between healthy and streptozotocin-induced diabetic rats. Additionally, the effect of sorafenib on glucose levels was investigated. METHODS: The rats were assigned to the groups: streptozotocin-induced diabetic (DG, n = 8) or healthy (HG, n = 8). The rats received sorafenib orally as a single dose of 100 mg/kg. The plasma concentrations of sorafenib and its metabolite N-oxide were measured with the validated high-performance liquid chromatography with ultraviolet detection. RESULTS: The difference between groups in Cmax and AUC0-t values for sorafenib were significant (p = 0.0004, p = 0.0104), and similarly for the metabolite (p = 0.0008, p = 0.0011). Greater exposure for the parent drug and analysed metabolite was achieved in diabetic group. However, the Cmax, AUC0-t, and AUC0-∞ ratios between the metabolite and sorafenib were similar in both groups. The significant reduction of glycaemia was observed only in the diabetic animals. CONCLUSION: The findings of the study provide evidence that diabetes significantly influence on the exposition for sorafenib and its metabolite, but similar ratios N-oxide/sorafenib for AUC and Cmax in healthy and diabetic animals suggest that oxidation of the TKI is rather unchanged. Additionally, sorafenib-associated hypoglycaemia was confirmed in diabetic animals.

Influence of obesity on pharmacokinetics and analgesic effect of ketoprofen administered intravenously to patients after laparoscopic cholecystectomy.

BACKGROUND: Ketoprofen is an analgesic drug commonly applied in the postoperative period, e.g., to patients after laparoscopic cholecystectomy. Many patients who undergo this procedure are obese. As pathophysiological changes are observed in obesity, the efficacy of ketoprofen may be altered in this group of patients. The aim of the study was to compare the pharmacokinetic parameters and analgesic effect of ketoprofen administered to obese and non-obese patients after laparoscopic cholecystectomy. METHODS: The study was conducted on 41 patients after laparoscopic cholecystectomy, who were divided into two groups: obese (n = 21) and non-obese (n = 20). Ketoprofen was administered intravenously at a dose of 100 mg. Plasma ketoprofen concentrations were measured by means of validated high-performance liquid chromatography with ultraviolet detection. The pharmacokinetic parameters of the drug were calculated using the non-compartmental method. Additionally, pain intensity was assessed during the study using NRS scale. RESULTS: The obese patients had significantly lower AUC0-∞ (1.4-fold), AUMC0-t (1.8-fold), AUMC0-∞ (3.2-fold), MRT0-t (1.4-fold), MRT0-∞ (2.3-fold), t0.5 (2.3-fold) and Vz/kg (2.3-fold) and higher kel (2.2-fold) than the non-obese group. Moreover, 4 h and 6 h after the administration of the drug, pain intensity was significantly higher in the obese patients. CONCLUSIONS: The drug was eliminated faster and the analgesic effect of ketoprofen in the obese patients was decreased as compared with the non-obese subjects. However, pain intensity did not increase to the level, which required additional analgesic treatment. Therefore, it seems that dosage adjustment of intravenous ketoprofen is not necessary in obese patients.

The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid.

Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (Cmax increase of 136.4% and 54.7% and AUC0-∞ increase of 53.7% and 86.5%, respectively). The Cmax of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.

Development of a UHPLC-MS/MS Method for the Determination of Quercetin in Milk and its Application to a Pharmacokinetic Study.

INTRODUCTION: Quercetin is a polyphenolic flavonoid which has been used in traditional Chinese medicine as a natural therapeutic agent with a broad spectrum of activities (antioxidant, anticancer, neuroprotective, anti-inflammatory, antiviral and antibacterial). The aim of this study was to develop and validate a rapid and simple ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method for the determination of quercetin in milk. MATERIAL AND METHODS: Sample preparation was based on a liquid-liquid extraction with 0.5% formic acid in acetonitrile. The chromatographic separation was performed on a ZORBAX SB-C18 column with methanol and 0.5% formic acid as a mobile phase. RESULTS: The procedure was successfully validated. The mean recovery of the analyte was 98%, with the corresponding intra- and inter-day variation less than 10% and 15%, respectively, and the repeatability and reproducibility were in the range of 3%-7.2% and 6.1%-12%, respectively. The lowest level of quantification was 1.0 µg/kg. CONCLUSION: The proposed method was successfully applied in evaluating the pharmacokinetics of quercetin in milk obtained from dairy cows with clinical mastitis after intramammary administration.

Influence of Obesity and Type 2 Diabetes Mellitus on the Pharmacokinetics of Tramadol After Single Oral Dose Administration.

BACKGROUND AND OBJECTIVES: The number of overweight, obese and diabetic patients is constantly increasing. Metabolic disorders may affect the pharmacokinetics of drugs, e.g., by altering the activity of cytochrome P450 (CYP) isoenzymes. Tramadol is a commonly used analgesic metabolised mainly via CYP2D6 to its active metabolite, O-desmethyltramadol. The aim of the study was to assess the influence of overweight, obesity and type 2 diabetes mellitus on tramadol and O-desmethyltramadol pharmacokinetics. METHODS: All patients received a single oral dose (100 mg) of tramadol. The plasma concentrations of tramadol and O-desmethyltramadol were measured with the validated high-performance liquid chromatography method with fluorescence detection. The pharmacokinetic parameters of tramadol and O-desmethyltramadol were calculated by non-compartmental methods. RESULTS: After nephrectomy, the patients were divided into four groups-a control group (n = 12, mean [SD] age 61 [14] years, body mass index (BMI) 22 [2] kg/m2, CLcr (creatinine clearance) 74 [30] mL/min); an overweight group (n = 15, mean [SD] age 63 [11] years, BMI 27 [1] kg/m2, CLcr 81 [35] mL/min); an obese group (n = 12, mean [SD] age 57 [8] years, BMI 33 [4] kg/m2, CLcr 113 [51] mL/min); and an obese and diabetic group (n = 9, mean [SD] age 64 [10] years, BMI 33 [4] kg/m2, CLcr 87 [35] mL/min). Apart from the time to first occurrence of maximal concentration (tmax), there were no significant differences in the pharmacokinetic parameters of tramadol and O-desmethyltramadol among the groups. Moreover, there were no significant differences in the O-desmethyltramadol/tramadol ratios among the four groups of patients after nephrectomy. CONCLUSIONS: No significant differences were found in the pharmacokinetics of tramadol and O-desmethyltramadol, indicating that the opioid can be administered to overweight, obese and diabetic patients without dosage adjustment.

Fluctuations in Pharmacokinetics Profiles of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) are a group of drugs with predicted slow linear and target-mediated distribution and elimination. Visual inspection of published pharmacokinetic profiles of mAbs frequently reveals plateaus in the distribution phase or an increasing concentration many days after a single intravenous dose. A question which has been left unanswered until now is whether mAbs undergo recirculation mechanisms. If so, then which mechanisms are crucial for the fluctuation in their pharmacokinetics profiles? What is the impact of such mechanisms on mAb absorption, distribution and elimination? Current commentary accounts for the fluctuation of mAbs concentrations based on different mechanisms, as well in different phases of their in vivo disposition. Current knowledge shows significant impact of mAbs lymphatic recirculation on characteristics of their pharmacokinetics profiles. Fluctuating or plateau phases in pharmacokinetic profiles of mAbs are a consequence of multiple simultaneously occurring recirculatory as well as adsorption/desorption processes rather than only slow, continuous elimination. Lymphatic recirculation as well as other mechanisms appears to be an obvious element of the mAbs disposition. Periodic changes in the key factors affecting mAbs disposition can be responsible for the unpredictable concentration peaks in absorption, distribution and the elimination phase.