Potential Drug-Drug Interactions among Patients with Schizophrenia Spectrum Disorders: Prevalence, Association with Risk Factors, and Replicate Analysis in 2021.

Background and Objectives: Patients with schizophrenia are often exposed to polypharmacotherapy, which may lead to drug-drug interactions. The aim of the study was to investigate the prevalence of potential drug-drug interactions (pDDIs) in hospitalized patients with schizophrenia spectrum disorders and to identify factors associated with pDDIs and manifested symptoms and signs. Materials and Methods: This cross-sectional observational study included 311 inpatients admitted to a psychiatric hospital. The LexiComp drug interaction program was used to identify pDDIs in 2014. Factors associated with the prevalence of pDDIs and factors related to clinically observed symptoms and signs were assessed using multivariable regression. In addition, replicate analysis of pDDI was performed using 2021 program updates. Results: The prevalence of pDDIs was 88.7%. Our study showed that more than half of the patients received at least one drug combination that should be avoided. The most common pDDIs involved combinations of two antipsychotics or combinations of antipsychotics and benzodiazepines, which can lead to cardio-respiratory depression, sedation, arrhythmias, anticholinergic effects, and neuroleptic malignant syndrome. The number of prescribed drugs was a risk factor for pDDIs (OR 2.85; 95% CI 1.84-5.73). All groups of clinically observed symptoms and signs were associated with the number of drugs. In addition, symptoms and signs characteristic of the nervous system and psychiatric disorders were associated with antipsychotic dosage (IRR 1.33; 95% CI 1.12-1.58), which could contribute to the development of extrapyramidal syndrome, insomnia, anxiety, agitation, and bipolar mania. The 2021 version of the drug interaction program showed a shift in drug interactions toward a lower risk rating, implying less severe patient management and possibly less alert fatigue. Conclusions: Patients with schizophrenia spectrum disorders are at high risk of developing drug-drug interactions. Optimization of drug therapy, patient monitoring, and use of drug interaction programs could help to prevent pDDIs and subsequent adverse drug events.

Adverse drug events during transitions of care : Randomized clinical trial of medication reconciliation at hospital admission.

BACKGROUND: During transitions of care, patient's medications are prone to medication errors. This study evaluated the impact of pharmacist-led medication reconciliation at hospital admission on unintentional medication discrepancies and adverse drug events. METHODS: A randomized controlled clinical trial was conducted in 120 adult medical patients hospitalized in a tertiary hospital in Slovenia. In the intervention group, a pharmacist-led medication reconciliation was performed on admission, while the control group received usual care. Patient's drug treatment before admission was compared with their admission and inpatient treatment to identify discrepancies. The intention of discrepancies and related adverse drug events were assessed as a consensus of an expert panel. RESULTS: Included patients were elderly (median 72 years) and treated with polypharmacy (median 7 medications). Upon admission, discrepancies and unintentional discrepancies, representing a medication error, were identified in 61.2% (825/1347) and 18.3% (247/1347) of medications, respectively. In the intervention group, only 29.1% (37/127) of unintentional discrepancies were reported to the physicians in person. The majority of admission discrepancies (88%) persisted through hospitalization. Unintentional discrepancies resulted in 51 adverse drug events even during hospitalization. There were no differences between the intervention and control group in the occurrence of unintentional discrepancies (p = 0.481) or adverse drug events (p = 0.801). CONCLUSIONS: Medication reconciliation at hospital admission failed to reduce unintentional discrepancies and adverse drug events, possibly due to its poor integration into clinical practice. Discrepancies resulted in patient harm even during the short period of hospitalization, which warrants the implementation of medication reconciliation at hospital admission.

Impact of clinical pharmacist's interventions on pharmacotherapy management in elderly patients on polypharmacy with mental health problems including quality of life: A prospective non-randomized study.

Mental health problems (MHPs) are very common in the elderly and can have an important influence on their quality of life (QoL). There is almost no data on the impact of clinical pharmacists' (CPs) interventions on the QoL including elderly patients and MHPs. The main aim of this study was to determinate the impact of (CP's) interventions on the QoL and quality of pharmacotherapy. A prospective non-randomized pre-post study was designed which included residents of a nursing home aged 65 age or more with at least one MHP. Each patient also filled out the EQ-5D questionnaire. The medical review MR included drug-related problems (DRPs) and potentially drug-drug interactions (pDDIs), as well as potentially inappropriate medications (PIMs). After 2 months, the participants were interviewed again. The mean number of medications before the intervention was 12,2 ± 3,1 per patient and decreased to 10,3 ± 3,0 medications per patient (p < 0,05) (n = 24). The total number of PIMs and pDDIs was also reduced and QoL was also significantly higher (p < 0,05). A collaborative care approach with a CP led to a decrease of DRPs, pDDIs, PIMs, the total number of medications and to an improvement in the patients' QoL.

Impact of drugs on venous thromboembolism risk in surgical patients.

PURPOSE: This review focuses on the most common drugs administered to surgical patients during the perioperative period that affect the risk of venous thromboembolism (VTE). RESULTS: Among analgesics, the risk of VTE is increased in patients treated with diclofenac, ibuprofen, and rofecoxib, but not naproxen, while metamizole can confer a protective effect. The relationship between sedatives and VTE has not been sufficiently studied. Tricyclic antidepressants, low-potency serotonin reuptake inhibitors, and antipsychotics have been associated with increased risk of VTE. The use of diuretics in the perioperative period is poorly researched; however, hyponatremia is considered a risk factor. Other factors that may influence the risk of VTE include bridging anticoagulation, allogeneic transfusion, and hemostatic management before surgery. Pharmacotherapy for HIV or cancer may also increase VTE risk. CONCLUSION: Increased monitoring for VTE is therefore advisable in surgical patients and those receiving antipsychotics, antidepressants, diuretics, or analgesics.

Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study.

PURPOSE: Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. METHODS: Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. RESULTS: A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. CONCLUSIONS: We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.

Prescribing patterns for inpatients with schizophrenia spectrum disorders in a psychiatric hospital in Slovenia: Results of 16-month prospective, non-interventional clinical research.

BACKGROUND: In Slovenia, there has been no evidence about the prescribing patterns for inpatients with psychotic disorders. The research aims to analyze drug utilization patterns for inpatients with psychotic disorder that are coded as F20-F29 according to International Classification of Diseases (ICD) 10th revision (schizophrenia spectrum disorders). SUBJECTS AND METHODS: Prospective research was conducted at the Psychiatric Hospital Idrija. The medical records of the inpatients admitted over a 12-month period were collected from the beginning to the end of their hospitalization. RESULTS: A total of 311 inpatients with 446 hospitalizations were included, producing a total of 3954 medication prescriptions. Medications prescribed pro re nata (the use of as needed) were also taken into account. Antipsychotics (N=1149, 43% of prescriptions) were the most often prescribed medications, followed by anxiolytics, antiparkinsonians, antidepressants, mood stabilizers and cardiovascular drugs. A total of 256 (82%) inpatients received at least one pro re nata medication. It was observed that the studied population was treated with one antipsychotic on 27 percent of prescriptions. CONCLUSIONS: Inpatients with schizophrenia spectrum disorders were exposed to a large number of different drugs. They were not received only psychotropic drugs but also other medications. With the knowledge about medications the implementation of clinical pharmacy services to the psychiatrists would significantly improve medication of inpatients with psychotic disorders and polypharmacotherapy.

Polypharmacotherapy and blood products as risk factors for venous thromboembolism in postsurgical patients: a case-control study.

Background After surgical procedures, patients are at high risk of developing venous thromboembolism, clinically manifested as deep vein thrombosis (DVT) or pulmonary embolism (PE). Objective To evaluate the influence of polypharmacotherapy, comorbidity, drug treatments, packed red blood cells application, adequacy of thromboprophylaxis, and patient characteristics on the occurrence of DVT or PE in postsurgical patients. Setting The surgical department at Murska Sobota General Hospital, Slovenia. Methods In this retrospective case control study, the records of 286 surgical patients were analysed: DVT or PE group (n = 144) and control group (n = 142). The number of prescribed drugs and drug-drug interactions were reviewed, together with prescription of low-molecular-weight heparins. The odds ratios (OR) of risk factors for DVT or PE were calculated using a multivariable logistic regression model. Main outcome measure Risk factors assessment for the occurrence of DVT or PE in surgical patients. Results Polypharmacotherapy (OR 2.02, 95% CI 1.03-3.96, p = 0.040) and packed red blood cells application (OR 3.44, 95% CI 1.46-8.10, p = 0.005) were associated with an increased risk of PE or DVT after surgery. Inadequate thromboprophylaxis with low-molecular-weight heparins significantly increased the likelihood of DVT or PE (OR 2.50, 95% CI 1.41-4.43, p = 0.002). There were no differences between the groups concerning the treatment with nonsteroidal anti-inflammatory drugs, benzodiazepines or antipsychotics. Conclusions Patients with polypharmacotherapy and patients receiving red blood cells should be monitored more closely after surgery as they are more likely to develop DVT or PE.

Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome.

AIMS: Pharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B-cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome. METHODS: Rituximab serum levels were determined by enzyme-linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling. RESULTS: The data were best described by a two-compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227-0.279] l day-1 and time-varying specific clearance of 0.278 (95% CI: 0.181-0.390) l day-1 , corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day-1 (95% CI: 0.0478-0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4-95.0). CONCLUSIONS: This finding indicates that time-changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients.

Influence of Prescribed Blood Products on the Incidence of Deep Vein Thrombosis and Pulmonary Embolism in Surgical Patients.

Deep vein thrombosis (DVT) and pulmonary embolisms (PEs) are common complications after surgical procedures. The influence of prescribed blood products on the occurrence of DVT and PE was evaluated in postsurgical patients in this retrospective case-control study. The records of 286 surgical patients were analyzed: DVT (n = 52), PE (n = 92), and a control group (n = 142). The amounts of prescribed blood, blood products, and vitamin K were reviewed, together with appropriate prescribing of low-molecular-weight heparins. The influence of prescribed blood products on the occurrence of DVT or PE was analyzed using multinomial logistic regression. We demonstrated a significant difference between the test and control groups ( P < .05) in relation to receiving packed red blood cells. Treatment with red blood cells was associated with an increased risk of PE but not DVT. Patients who developed PE after surgery were hospitalized for longer (median 10 days) than patients with DVT (median 6 days). There was no difference between the test and control groups concerning treatment with fresh frozen plasma. Inadequate thromboprophylaxis significantly increased the likelihood of DVT. There is a connection between receiving packed red blood cells and occurrence of postoperative PE in surgical patients. Thus, patients receiving red blood cells should be monitored more closely after surgery, as they are more likely to develop PE postoperatively.

A simple dried blood spot method for clinical pharmacological analyses of etoposide in cancer patients using liquid chromatography and fluorescence detection.

BACKGROUND: Therapeutic drug monitoring of etoposide is not part of the routine clinical practice, however, measuring etoposide plasma concentration may be useful to prevent chemotherapy related adverse drug reactions. This paper describes the development and validation of a dried blood spot (DBS) assay for the determination of etoposide in blood samples of lung cancer patients. METHODS: The whole blood spot was cut out of the DBS card followed by sonication assisted liquid drug extraction. Extraction solution was evaporated and re-dissolved. A high-performance-liquid-chromatography method with fluorimetric detection ( λex=230nm; λem=330nm) was used. RESULTS: Method met the validation criteria in terms of selectivity, linearity (0.5-20.0µg/mL), accuracy (≥96.1%), precision (≤10.1%) and stability (long term 4weeks at room temperature and 40°C). Haematocrit did not influence DBS etoposide concentration. Good correlation between measured plasma and DBS concentrations was observed. The equation considering only haematocrit value was used for conversion of DBS to plasma concentration. CONCLUSIONS: DBS sampling method showed comparable results to plasma samples. Therefore, it can be concluded that the developed and validated DBS method, which is more patient-friendly and requires less sample handling, is a reliable alternative to conventional plasma methods for measuring etoposide concentration in clinical pharmacological analyses.

Efflux and uptake transporters involved in the disposition of bazedoxifene.

Bazedoxifene, a novel selective estrogen receptor modulator, has complex pharmacokinetics with rapid absorption, high metabolic clearance, low oral bioavailability (6.25 %) and a slow elimination phase. Our hypothesis is that drug uptake and efflux transporters may play an important role in its disposition. To adequately cover all aspects of bazedoxifene transport, several approaches were undertaken: PAMPA assay, ATPase assay, membrane inside-out vesicles and Caco-2 and CHO cell lines. The results obtained from PAMPA experiments showed moderate passive permeability of bazedoxifene (P app ≈ 2 × 10(-6)cm/s), suggesting the existence of an active transport during the rapid absorption phase. The Caco-2 transport assay showed large and significant changes in the measured efflux ratios of bazedoxifene when selective transporter inhibitors were applied: verapamil (a Pgp inhibitor), MK571 (an MRP inhibitor), Ko143 (a BCRP inhibitor) and DIDS (an OATP inhibitor). Additionally, membrane preparation experiments demonstrated the interaction of bazedoxifene with P-gp, MRP2 and BCRP. CHO experiments did not show any interactions of bazedoxifene with OATP1B1 or OATP1B3; therefore, bazedoxifene may be a substrate of other OATP isoform(s). The comprehensive in vitro study indicates a strong involvement of Pgp, MRP, BCRP and OATP in bazedoxifene disposition.

Febrile neutropenia in chemotherapy treated small-cell lung cancer patients.

BACKGROUND: Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients. METHODS: The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored. RESULTS: Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia. CONCLUSIONS: Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.

Potential drug-drug interactions in hospitalized patients with chronic heart failure and chronic obstructive pulmonary disease.

INTRODUCTION: Polypharmacy is common in patients with chronic heart failure (HF) and/or chronic obstructive pulmonary disease (COPD), but little is known about the prevalence and significance of drug-drug interactions (DDIs). This study evaluates DDIs in hospitalized patients. MATERIAL AND METHODS: We retrospectively screened medical charts over a 6-month period for diagnosis of chronic HF and/or COPD. Potential DDIs were evaluated using Lexi-Interact software. RESULTS: Seven hundred and seventy-eight patients were included in the study (median age 75 years, 61% men). The median number of drugs on admission and discharge was 6 (interquartile range (IQR) 4-9) and 7 (IQR 5-), respectively (p = 0.10). We recorded 6.5 ±5.7 potential DDIs per patient on admission and 7.2 ±5.6 on discharge (p = 0.2). From admission to discharge, type-C and type-X potential DDIs increased (p < 0.05 for both). Type X interactions were rare (< 1%), with the combination of a ß-blocker and a ß2 agonist being the most common (64%). There were significantly more type-C and type-D potential DDIs in patients with chronic HF as compared to patients with COPD (p < 0.001). Patients with concomitant chronic HF and COPD had more type-C and type-X potential DDIs when compared to those with individual disease (p < 0.005). An aldosterone antagonist and ACE inhibitor/ARB were prescribed to 3% of chronic HF patients with estimated glomerular filtration rate < 30 ml/(min × 1.73 m(2)). CONCLUSIONS: The DDIs are common in patients with chronic HF and/or COPD, but only a few appear to be of clinical significance. The increase in potential DDIs from admission to discharge may reflect better guideline implementation rather than poor clinical practice.

Inverse correlation of carotid intima-media thickness with raloxifene serum levels in osteoporosis.

BACKGROUND: Raloxifene is a selective oestrogen receptor modulator with effects on bone and breast cancer and cardiovascular disease risk. The aim of this study was to examine the influence of raloxifene treatment on surrogate markers of atherosclerosis and the correlation of these markers with raloxifene serum concentrations. METHODS: A prospective clinical trial on 53 postmenopausal osteoporotic women treated with raloxifene was performed. Surrogate markers of atherosclerosis (flow-mediated vasodilatation, glyceryltrinitrate-induced vasodilatation of the brachial artery, carotid intima-media thickness (c-IMT), inter-cell adhesion molecule-1, vascular-cell adhesion molecule-1 and E-selectin) were measured before and after 6 months of treatment. Serum concentrations of raloxifene and raloxifene metabolites were assessed after 12 months of treatment. The tested markers were correlated with measured serum concentrations of raloxifene species. RESULTS: Among the tested surrogate markers of atherosclerosis c-IMT, E-selectin and ICAM changed significantly during treatment. A negative correlation of the non-metabolized raloxifene serum levels with the percentage change of c-IMT during treatment (r = - 0.315, p = 0.048) was found. Likewise, the sum of the levels of three raloxifene metabolites, raloxifene-6-b-glucuronide (M1), raloxifene-4'-b-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3) in serum showed a negative correlation with the percentage change of c-IMT during treatment (r = - 0.375, p = 0.017). For the other tested parameters, no correlation with raloxifene serum levels was found. CONCLUSIONS: To the best of our knowledge, this is the first study correlating raloxifene species serum concentrations with changes in the surrogate markers of atherosclerosis. A greater decrease of c-IMT in patients with higher raloxifene concentrations could contribute to a lower risk of cardiovascular events in these patients.

High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients.

OBJECTIVE: Mycophenolic acid (MPA) exposure is associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients. Various drug interaction studies, predominantly in healthy volunteers or solid organ transplant recipients, have identified medications which impact MPA pharmacokinetics. Recipients of nonmyeloablative HCT, however, have an increased burden of comorbidities, potentially increasing the number of concomitant medications and potential drug interactions (PDI) affecting MPA exposure. Thus, we sought to be the first to characterize these PDI in nonmyeloablative HCT recipients. MATERIALS AND METHODS: We compiled PDI affecting MPA pharmacokinetics and characterized the prevalence of PDI in nonmyeloablative HCT recipients. A comprehensive literature evaluation of four databases and PubMed was conducted to identify medications with PDI affecting MPA pharmacokinetics. Subsequently, a retrospective medication review was conducted to characterize the cumulative PDI burden, defined as the number of PDI for an individual patient over the first 21 days after allogeneic graft infusion, in 84 nonmyeloablative HCT recipients. RESULTS: Of the 187 concomitant medications, 11 (5.9%) had a PDI affecting MPA pharmacokinetics. 87% of 84 patients had one PDI, with a median cumulative PDI burden of 2 (range 0 - 4). The most common PDI, in descending order, were cyclosporine, omeprazole and pantoprazole. CONCLUSION: Only a minority of medications (5.9%) have a PDI affecting MPA pharmacokinetics. However, the majority of nonmyeloablative HCT recipients had a PDI, with cyclosporine and the proton pump inhibitors being the most common. A better understanding of PDI and their management should lead to safer medication regimens for nonmyeloablative HCT recipients.

Oral treatment with etoposide in small cell lung cancer - dilemmas and solutions.

BACKGROUND: Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity. CONCLUSIONS: The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.

Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment.

Raloxifene exhibits a large and unexplained interindividual variability in its pharmacokinetics and pharmacodynamics. The aim of our study was to identify transporters involved in the efflux of raloxifene and its glucuronide metabolites by various in vitro models and by an in vivo study to explore the possible involvement of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP)1, MRP2, MRP3, and breast cancer resistance protein in the observed high interindividual variability. Experiments with the parallel artificial membrane permeability assay showed the highest passive permeability for raloxifene, followed by raloxifene-6-ß-glucuronide (M1), raloxifene-4'-ß-glucuronide (M2), and raloxifene-6,4'-diglucuronide (M3). Caco-2 cell monolayer experiments indicated an interaction of raloxifene with Pgp. The ATPase assay confirmed the raloxifene interaction with Pgp and indicated interactions of all raloxifene species with MRP1, MRP2, MRP3, and breast cancer resistance protein, except for M1, which did not show any interactions with MRP2. Furthermore, the vesicular experiments confirmed the interaction of M2 and M3 with MRP2. Although the in vivo study on osteoporotic postmenopausal women on raloxifene could not confirm a significant influence of ABCB1 and ABCC2 genetic polymorphisms on its pharmacokinetics, a clear trend toward higher total raloxifene concentrations was observed in carriers of at least 1 ABCB1 c.3435T allele. Moreover, the same polymorphism effect was also observed as a significant increase in total hip bone mineral density after 1 year of treatment. The results of our study support the involvement of efflux transporters in disposition of raloxifene and its metabolites and may partially explain the observed raloxifene variability by the influence of the ABCB1 c.3435C>T polymorphism.

Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene.

BACKGROUND: Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic-anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. METHODS: To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. RESULTS: Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-ß-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. CONCLUSIONS: These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene.

In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes.

Bazedoxifene is a selective estrogen receptor modulator (SERM) that has been developed for use in post-menopausal osteoporosis. However, it contains a potentially toxic 5-hydroxy-3-methylindole moiety. Previous studies on the 5-hydroxyindole and the 3-alkylindole-containing drugs indometacine, zafirlukast and MK-0524 structural analogs have shown that they are bioactivated by cytochrome P450s through a dehydrogenation process to form quinoneimine or 3-methyleneindolenine electrophilic species. In the present study, bazedoxifene was synthesized and then evaluated, together with raloxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (13), a 3-methyl-5-hydroxyindole-based structural fragment of bazedoxifene, for its ability to form reactive electrophilic species when incubated with human liver microsomes (HLMs) or recombinant CYP isozymes. We showed that bazedoxifene was bioactivated only in trace amounts with recombinant CYP isozymes. In contrast, the N-dealkylated fragment of bazedoxifene (2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) was bioactivated in considerable amounts to an electrophilic intermediate, which was trapped with glutathione and identified by LC-MS/MS. This suggests that bazedoxifene would require initial N-dealkylation, which could subsequently lead to the formation of the reactive intermediate. However, such an N-dealkylated metabolite of bazedoxifene was not detected after the incubation of bazedoxifene in HLM or recombinant CYP isozymes.

Raloxifene glucuronidation in human intestine, kidney, and liver microsomes and in human liver microsomes genotyped for the UGT1A1*28 polymorphism.

Raloxifene, a selective estrogen receptor modulator, exhibits quite large interindividual variability in pharmacokinetics and pharmacodynamics. In women, raloxifene is metabolized extensively by different isoforms of UDP-glucuronosyltransferase (UGT) to its glucuronides. To gain an insight into intestine, kidney, liver, and lung glucuronidation of raloxifene, human microsomes of all tested organs were used. Raloxifene-6-ß-glucuronide (M1) formation followed the Michaelis-Menten kinetics in intestinal, kidney, and liver microsomes; meanwhile, raloxifene-4'-ß-glucuronide (M2) formation followed the substrate inhibition kinetics. Human lung microsomes did not show any glucuronidation activity. The tissue intrinsic clearances for kidney, intestine, and liver were 3.4, 28.1, and 39.6 ml · min(-1) · kg(-1), respectively. The aim of our in vitro study was to explain the mechanism behind the observed influence of UGT1A1*28 polymorphism on raloxifene pharmacokinetics in a small-sized in vivo study (Br J Clin Pharmacol 67:437-444, 2009). Incubation of raloxifene with human liver microsomes genotyped for UGT1A1*28 showed a significantly reduced metabolic clearance toward M1 in microsomes from donors with *28 allele. On the contrary, no significant genotype influence was observed on the formation of M2 because of the high variability in estimated apparent kinetic parameters, although a clear trend toward lower glucuronidation activities was observed when UGT1A1*28 polymorphism was present. The liver intrinsic clearances of both homozygotes differed significantly, whereas the clearance of heterozygotes did not differ from the wild-type and the mutated homozygotes. In conclusion, our results show the high importance of the liver and intestine in raloxifene glucuronidation. Moreover, the significant influence of UGT1A1*28 polymorphism on metabolism of raloxifene was confirmed.