Digital Care Pathway for Patients With Sleep Apnea in Specialized Care: Mixed Methods Study.

BACKGROUND: Sleep apnea is a significant public health disorder in Finland, with a prevalence of 3.7%. Continuous positive airway pressure (CPAP) therapy is the first-line treatment for moderate or severe sleep apnea. From November 18, 2019, all patients who started their CPAP therapy at Oulu University Hospital were attached to a sleep apnea digital care pathway (SA-DCP) and were instructed on its use. Some patients still did not use the SA-DCP although they had started their CPAP therapy. OBJECTIVE: We aimed to study health care professionals' (HCPs') perspectives on the SA-DCP and its usefulness for their work; whether the main targets of SA-DCP can be reached: shortening the initial guiding sessions of CPAP therapy, reducing patient calls and contact with HCPs, and improving patients' adherence to CPAP therapy; and patients' perspectives on the SA-DCP and its usefulness to them. METHODS: Overall, 6 HCPs were interviewed in May and June 2021. The survey for SA-DCP users (58/91, 64%) and SA-DCP nonusers (33/91, 36%) was conducted in 2 phases: from May to August 2021 and January to June 2022. CPAP device remote monitoring data were collected from SA-DCP users (80/170, 47.1%) and SA-DCP nonusers (90/170, 52.9%) in May 2021. The registered phone call data were collected during 2019, 2020, and 2021. Feedback on the SA-DCP was collected from 446 patients between February and March 2022. RESULTS: According to HCPs, introducing the SA-DCP had not yet significantly improved their workload and work practices, but it had brought more flexibility in some communication situations. A larger proportion of SA-DCP users familiarized themselves with prior information about CPAP therapy before the initial guiding session than nonusers (43/58, 74% vs 16/33, 49%; P=.02). Some patients still had not received prior information about CPAP therapy; therefore, most of the sessions were carried out according to their needs. According to the patient survey and remote monitoring data of CPAP devices, adherence to CPAP therapy was high for both SA-DCP users and nonusers. The number of patients' phone calls to HCPs did not decrease during the study. SA-DCP users perceived their abilities to use information and communications technology to be better than nonusers (mean 4.2, SD 0.8 vs mean 3.2, SD 1.2; P<.001). CONCLUSIONS: According to this study, not all the goals set for the introduction of the SA-DCP have been achieved. Despite using the SA-DCP, some patients still wanted to communicate with HCPs by phone. The most significant factors explaining the nonuse of the SA-DCP were lower digital literacy and older age of the patients. In the future, more attention should be paid to these user groups when designing and introducing upcoming digital care pathways.

Reporting of costs and economic impacts in randomized trials of de-implementation interventions for low-value care: a systematic scoping review.

BACKGROUND: De-implementation of low-value care can increase health care sustainability. We evaluated the reporting of direct costs of de-implementation and subsequent change (increase or decrease) in health care costs in randomized trials of de-implementation research. METHODS: We searched MEDLINE and Scopus databases without any language restrictions up to May 2021. We conducted study screening and data extraction independently and in duplicate. We extracted information related to study characteristics, types and characteristics of interventions, de-implementation costs, and impacts on health care costs. We assessed risk of bias using a modified Cochrane risk-of-bias tool. RESULTS: We screened 10,733 articles, with 227 studies meeting the inclusion criteria, of which 50 included information on direct cost of de-implementation or impact of de-implementation on health care costs. Studies were mostly conducted in North America (36%) or Europe (32%) and in the primary care context (70%). The most common practice of interest was reduction in the use of antibiotics or other medications (74%). Most studies used education strategies (meetings, materials) (64%). Studies used either a single strategy (52%) or were multifaceted (48%). Of the 227 eligible studies, 18 (8%) reported on direct costs of the used de-implementation strategy; of which, 13 reported total costs, and 12 reported per unit costs (7 reported both). The costs of de-implementation strategies varied considerably. Of the 227 eligible studies, 43 (19%) reported on impact of de-implementation on health care costs. Health care costs decreased in 27 studies (63%), increased in 2 (5%), and were unchanged in 14 (33%). CONCLUSION: De-implementation randomized controlled trials typically did not report direct costs of the de-implementation strategies (92%) or the impacts of de-implementation on health care costs (81%). Lack of cost information may limit the value of de-implementation trials to decision-makers. TRIAL REGISTRATION: OSF (Open Science Framework): https://osf.io/ueq32 .

Implementation of a new Digi-HTA process for digital health technologies in Finland.

OBJECTIVES: There has been a lack of health technology assessment (HTA) methods for novel digital health technologies (DHTs) such as mHealth, artificial intelligence, and robotics in Finland. The Digi-HTA method has been developed for this purpose. The aim of this study is to determine whether it would be possible to use Digi-HTA recommendations to support healthcare decision-makers. Secondly, from the perspective of companies offering different types of DHT products, this study assesses the suitability of using the Digi-HTA framework to perform HTAs for their products. METHODS: Feedback about Digi-HTA recommendations was collected from healthcare professionals. DHT companies provided input about the Digi-HTA framework. Data were collected via a web-based survey and were analyzed using qualitative methods. RESULTS: Of the twenty-four healthcare professional respondents, twenty said that the Digi-HTA recommendations contained all the necessary information, and twenty-one found them useful for their work. Respondents hoped that the Digi-HTA recommendations would be better integrated into the decision-making processes and healthcare professionals would be more informed about this new HTA process. The questions of the Digi-HTA framework were applicable for different DHT products based on the responses from DHT companies (n = 8). CONCLUSIONS: According to the study participants, although the Digi-HTA recommendations include clear and beneficial information, their integration into healthcare decision-making processes should be improved. Responses from DHT companies indicate that the Digi-HTA framework would be an appropriate tool for performing assessments for their products. To generalize the findings of this study, more comprehensive studies will be needed.

Characteristics and predictors of off-label use of antipsychotics in general population sample.

OBJECTIVE: Increasing number of people have been prescribed antipsychotics (APs) off-label in recent decades. This study aimed to identify the characteristics and predictors of receiving prescription of antipsychotics off-label. METHODS: The study sample was part of the Northern Finland Birth Cohort 1966 (n = 7071). Data included questionnaires and national register data. Information on prescribed medications was extracted from the national register. The sample was divided into three groups: Persons who had been prescribed APs off-label (n = 137), individuals with non-psychotic mental disorders without APs off label (n = 1478) and individuals who had been diagnosed with psychosis or bipolar disorder and who had been prescribed APs (n = 151). We compared sociodemographic, lifestyle and clinical characteristics between the off-label and the comparison groups using logistic regression. RESULTS: The most common diagnoses in the off-label group were depression (n = 96, 70.1%) and anxiety (n = 55, 40.1%). Compared with individuals with non-psychotic mental disorders who were not prescribed APs off-label, individuals with prescribed off-label APs had a lower level of education, lower socioeconomic status, were less often married, had a higher level of somatic and psychiatric morbidity, were more often smokers and more often had a substance abuse disorder and heavy alcohol consumption. When comparing the off-label group to individuals with psychosis or bipolar disorder who used APs, there were less differences, though individuals with psychosis or bipolar disorder had more markers of morbidity and a lower level of education. CONCLUSION: Individuals who had been prescribed APs off label had a higher level of mental and somatic morbidity and poorer socioeconomic status than individuals with non-psychotic mental disorders who did not use APs.

Detecting Patient Safety Errors by Characterizing Incidents Reported by Medical Imaging Staff.

The objectives of the study were to characterize events related to patient safety reported by medical imaging personnel in Finland in 2007-2017, the number and quality of reported injuries, the risk assessment, and the planned improvement of operations. The information was collected from a healthcare patient safety incident register system. The data contained information on the nature of the patient safety errors, harms and near-misses in medical imaging, the factors that lead to the events, the consequences for the patient, the level of risks, and future measures. The number of patient safety incident reports included in the study was 7,287. Of the incident reports, 75% concerned injuries to patients and 25% were near-misses. The most common consequence of adverse events and near-misses were minor harm (37.2%) related to contrast agent, or no harm (27.9%) related to equipment malfunction. Supervisors estimated the risks as low (47.7%) e.g., data management, insignificant (35%) e.g., verbal communication or moderate (15.7%) e.g., the use of contrast agent. The most common suggestion for learning from the incident was discussing it with the staff (58.1%), improving operations (5.7%) and submitting it to a higher authority (5.4%). Improving patient safety requires timely, accurate and clear reporting of various patient safety incidents. Based on incident reports, supervisors can provide feedback to staff, develop plans to prevent accidents, and monitor the impact of measures taken. Information on the development of occupational safety should be disseminated to all healthcare professionals so that the same mistakes are not repeated.

Investigating errors in medical imaging: medical malpractice cases in Finland.

OBJECTIVE: The objectives of the study were to survey patient injury claims concerning medical imaging in Finland in 1991-2017, and to investigate the nature of the incidents, the number of claims, the reasons for the claims, and the decisions made concerning the claims. MATERIALS AND METHODS: The research material consisted of patient claims concerning imaging, sent to the Finnish Patient Insurance Centre (PVK). The data contained information on injury dates, the examination code, the decision code, the description of the injury, and the medical grounds for decisions. RESULTS: The number of claims included in the study was 1054, and the average number per year was 87. The most common cause was delayed diagnosis (404 claims, 38.3%). Most of the claims concerned mammography (314, 29.8%), radiography (170, 16.1%), and MRI (162, 15.4%). According to the decisions made by the PVK, there were no delays in 54.6% of the examinations for which claims were made. About 30% of all patient claims received compensation, the most typical reason being medical malpractice (27.7%), followed by excessive injuries and injuries caused by infections, accidents and equipment (2.7%). CONCLUSION: Patient injury in imaging examinations and interventions cannot be completely prevented. However, injury data are an important source of information for health care. By analysing claims, we can prevent harm, increase the quality of care, and improve patient safety in medical imaging.

Inhibition and induction of CYP enzymes in humans: an update.

The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug-drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug-drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.

CYP-associated drug-drug interactions: A mission accomplished?

On the basis of official Finnish Medicines Authority (Fimea)-approved drug monographs, less than half of the approved small-molecule drugs between 2007 and 2016 were substrates, inhibitors or inducers of CYP enzymes, predominantly of CYP3A4. No significant unexpected, life-threatening, CYP-associated drug-drug interactions (CYP-DDIs) of newly approved drug entities have been observed in the last 10-15 years. The present analysis seems to suggest that tools to study and predict potentially significant CYP-DDIs are working and efficient.

Single-Arm Clinical Trials as Pivotal Evidence for Cancer Drug Approval: A Retrospective Cohort Study of Centralized European Marketing Authorizations Between 2010 and 2019.

The traditional drug development paradigm, consisting of sequential phases and randomized studies, has been challenged in oncology and hemato-oncology. In the regulatory context, a number of new products have been authorized based on nonrandomized efficacy and safety data. We retrospectively analyzed the European public assessment reports for anticancer treatments authorized between 2010 and 2019 to describe the data behind such approvals. Twenty-two initial marketing authorizations, mainly conditional, were identified. Fifty percent of the products had an orphan indication, and 77% had received previous scientific advice. Conclusions of clinical benefit were based on tumor responses, ranging between 15.8 and 88%. Our data shows that single-arm clinical studies leading to positive regulatory outcomes share common methodological approaches and end points, mostly comparing the overall response rate with a fixed success threshold as the primary analysis. The clinical indications in these approvals are clustered in late-line settings, hematological malignancies, and lung cancer. Our findings underline the need to reflect on the current practice, the methodological aspects, and end points in single-arm studies, and develop specific regulatory guidance on nonrandomized and novel study designs.

The Risks and Outcomes Resulting From Medication Errors Reported in the Finnish Tertiary Care Units:: A Cross-Sectional Retrospective Register Study.

Background: Hospital-acquired medication errors (MEs) are common in health care. Although voluntary reporting is criticized for not producing reliable estimates on ME frequency, it provides valuable knowledge on errors occurring in the medication process. Objective: The purpose of this study was to analyze and determine the risks and outcomes resulting from MEs related to the TOP15 medicines in the Finnish tertiary care units from July 2016 to July 2017. Methods: The data consisting of 1,447 ME reports was organized according to ATC classification, after which TOP15 medicines involved in the reports were selected. Inductive content analysis was performed to the reports. After this, the reports were categorized by ME outcome into five categories and further analyzed accordingly. Results: The most common ME outcome in the reports was "omitted medicine" (33.9%). More than a quarter (27.1%) of ME reports were estimated to cause moderate or severe risk to the patient. When compared with each other, none of the outcome groups were more susceptible to high-risk events (p = 0.71). Of the TOP15 medicines, only Norepinephrine had significantly higher risk of being involved in high-risk events (OR 2.43, 95%CI 1.35-4.61). Conclusion: Voluntary reporting has an important role in the development of medication safety and the overall medication process within organizations. Although majority of the TOP15 medicines were involved in MEs resulting in seemingly high-risk outcomes, they were estimated to be insignificant or minor within the reporting unit. In the future, more emphasis will be needed for the assessment and analysis of the reports for more efficient, real-time detection and response to signals from health care units.

Quantitative analysis of 4ß- and 4α­hydroxycholesterol in human plasma and serum by UHPLC/ESI-HR-MS.

Cholesterol oxidation product 4ß­hydroxycholesterol (4ß­OHC) may possibly be used as an endogenous biomarker of CYP3A enzyme activity and as CYP3A4 is involved in the metabolism of approximately 50% of the drugs in clinical use, the monitoring of CYP3A activity by 4ß­OHC plasma or serum levels, may be of clinical significance. The plasma and serum concentrations of 4α­hydroxycholesterol (4α­OHC), an isomer of 4ß­OHC, increase during uncontrolled storage conditions and therefore serve as an indicator of proper handling of samples. A sensitive and simple high-throughput method for the simultaneous quantification of both 4α­OHC and 4ß­OHC in human plasma and serum was developed utilizing ultrahigh performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC/ESI-HR-MS). The chromatographic analysis was carried out on a Waters HSS T3 C18 reversed phase column with a mobile phase composed of 0,1% formic acid with 200 mg/l sodium acetate, and methanol. 4ß­OHC and 4α­OHC and also internal standard d7­4ß­OHC were monitored using HR-MS as sodium adducts, which could not be used as a precursor ions in conventional tandem mass spectrometry methods due to their extensive stability in collision for MS/MS. The use of HR-MS detection enabled avoiding laborious sample derivatization, which is required with triple quadrupole mass spectrometer-based methods to achieve adequate analytical sensitivity for 4ß­OHC, as the underivatized molecule is otherwise poorly ionized to other molecular ions than sodium adduct. Chromatographic separation of 4α­OHC and 4ß­OHC was obtained and confirmed with standard samples prepared in blank surrogate matrix. The lower limits of quantitation in the assay were 0.5 ng/ml for 4ß­OHC, and 2 ng/ml for 4α­OHC. Endogenous levels of 4ß­OHC can vary between 10 and 100 ng/ml depending on the possible induction or inhibition of CYP3A4, whereas the levels of 4α­OHC can vary between 5 and 100 ng/ml, depending on the storage conditions of the samples. Thus, the sensitivity of the assay developed allows for the simultaneous measurement of endogenous levels of 4α­OHC and 4ß­OHC cost-effectively and with high throughput. The method was successfully used for the determination of 4ß­OHC and 4α­OHC concentrations in clinical plasma and serum samples collected before and after treatment with a known CYP3A4 inducer rifampicin. The endogenous levels in clinical human samples before treatment varied between 13.4 and 31.9 ng/ml for 4ß­OHC, and between 3.53 and 5.65 ng/ml for 4α­OHC, and a three-fold increase in 4ß­OHC plasma levels was observed after the rifampicin treatment, while 4α­OHC levels remained unaffected.

Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study.

BACKGROUND: Dipeptidyl peptidase 4 inhibitors (DPP4is) used to treat diabetes have been reported to be associated with an increased risk of bullous pemphigoid (BP). There are no previous reports analyzing the risk of BP in patients who are using other diabetes medications. OBJECTIVE: To evaluate the association between diabetes medications other than DPP4i and development of BP. METHODS: We investigated the prevalence of diabetes among patients with BP and the association between the use of diabetes drugs (excluding DPP4i, metformin, and insulin) and BP by analyzing national Finnish registry data for 3397 patients with BP and 12,941 patients with basal cell carcinoma as controls. RESULTS: Our results show that 19.6% of patients with BP have type 2 diabetes. Use of none of the investigated medications was associated with an increased risk of BP. LIMITATIONS: Because this was a registry-based study, it was not possible to verify the accuracy of the diagnoses. The risk of BP in users of glucagon-like peptide 1 receptor agonists could not be analyzed. CONCLUSION: Our study shows that the investigated diabetes drugs are not associated with an increased risk of BP in a Finnish patient database, indicating they can be safely used in this population. Generalization of these results to other populations will require further study.

New study designs in clinical drug development.

Clinical development of a novel drug has traditionally been seen as a series of four phases, each having its own objectives in establishing the efficacy and safety of the drug. Increasingly individualized medicine and the changing mechanisms of drug action are also changing the designs of clinical drug testing. The borders of development phases become blurred and the traditional large, controlled multicenter studies may in part be replaced by individual and risk-based approaches. The indications for drugs are more precisely targeted from biological starting points, and a target-oriented development may guide the designs of clinical testing at all stages of development. Utilization of data from registries along with modeling will become more common in clinical drug testing.

Hospitalizations Due to Adverse Drug Events in the Elderly-A Retrospective Register Study.

Adverse drug events (ADEs) are more likely to affect geriatric patients due to physiological changes occurring with aging. Even though this is an internationally recognized problem, similar research data in Finland is still lacking. The aim of this study was to determine the number of geriatric medication-related hospitalizations in the Finnish patient population and to discover the potential means of recognizing patients particularly at risk of ADEs. The study was conducted retrospectively from the 2014 emergency department patient records in Oulu University Hospital. A total number of 290 admissions were screened for ADEs, adverse drug reactions (ADRs) and drug-drug interactions (DDIs) by a multi-disciplinary research team. Customized Naranjo scale was used as a control method. All admissions were categorized into "probable," "possible," or "doubtful" by both assessment methods. In total, 23.1% of admissions were categorized as "probably" or "possibly" medication-related. Vertigo, falling, and fractures formed the largest group of ADEs. The most common ADEs were related to medicines from N class of the ATC-code system. Age, sex, residence, or specialty did not increase the risk for medication-related admission significantly (min p = 0.077). Polypharmacy was, however, found to increase the risk (OR 3.3; 95% CI, 1.5-6.9; p = 0.01). In conclusion, screening patients for specific demographics or symptoms would not significantly improve the recognition of ADEs. In addition, as ADE detection today is largely based on voluntary reporting systems and retrospective manual tracking of errors, it is evident that more effective methods for ADE detection are needed in the future.

Tandem mass spectrometric analysis of S- and N-linked glutathione conjugates of pulegone and menthofuran and identification of P450 enzymes mediating their formation.

RATIONALE: Menthofuran is a hepatotoxin and a major metabolite of pulegone, a monoterpene found in the essential oils of many mint species. It is bioactivated by cytochrome P450 (CYP) enzymes to reactive metabolites, which may further react with glutathione to form S-linked and N-linked conjugates. The tandem mass spectrometric (MS/MS) fragmentation pathways of rarely observed N-linked conjugates, and the differences to fragmentation of S-linked conjugates, have not been reported in the literature previously, although this information is essential to enable comprehensive MS/MS-based screening methods covering the both types of conjugates. METHODS: (R)-(+)-Pulegone, (S)-(-)-pulegone, and menthofuran were incubated with a human liver S9 fraction with glutathione (GSH) as the trapping agent. Conjugates were searched with ultra-performance liquid chromatography (UPLC)/orbitrap MS and their MS/MS spectra were measured both in the negative and positive ionization polarities. Menthofuran was also incubated with recombinant human CYP enzymes and GSH to elucidate the CYPs responsible for the formation of the reactive metabolites. RESULTS: Four GSH conjugates of menthofuran were detected and identified as S- and N-linked conjugates based on MS/MS spectra. N-linked conjugates lacked the characteristic fragments of S-linked conjugates and commonly produced fragments that retained parts of glutamic acid. CYP1A2, 2B6 and 3A4 were observed to produce more GSH conjugates than other CYP isoforms. CONLUSIONS: Furans can form reactive aldehydes that react in Schiff-base fashion with the free glutamyl-amine of GSH to form N-linked conjugates that have distinct MS/MS spectra from S-linked adducts. This should be taken into account when setting up LC/MS/MS-based detection of glutathione conjugates to screen for reactive metabolites, at least for compounds with a furan moiety. Neutral loss scanning of 178.0412 Da and 290.0573 Da in the positive ionization mode, or neutral loss scanning of 256.0695 Da and 290.0573 Da and precursor ion scanning of m/z 143.0462 in the negative ionization mode, is recommended. Copyright © 2016 John Wiley & Sons, Ltd.

Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species.

BACKGROUND: Metabolite profiles of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, were surveyed as part of its development. METHODS: The pharmacokinetics of ospemifene and its two major, pharmacologically active metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene, was elucidated in studies of volunteer humans given various doses of ospemifene and in experiments of several animal species (rat, mouse, dog, and cynomolgus monkey), which had been used either for pharmacological or toxicological studies of ospemifene. Metabolites produced in in vitro human and animal liver preparations were compared between species and with the metabolite profiles in the in vivo investigations. RESULTS: Considerable interspecies differences were observed in the metabolite profiles and quantities. The major human metabolite, 4-hydroxyospemifene, was produced in substantial amounts both in vitro and in vivo in most animal species, except dog, and thus the exposure to this metabolite seems adequate in the most important toxicology species, the rat and the cynomolgus monkey. 4'-Hydroxyospemifene was equally abundant in vitro and in vivo metabolite in mice and dogs, and consequently, its contribution to the total exposure of ospemifene-related activity would be adequately covered in animal experiments. Other ospemifene metabolites were variably detected in different species, but probably they are not of consequence to pharmacology or toxicology of ospemifene. CONCLUSIONS: Overall, there are quantitative and also some qualitative differences in the metabolism of ospemifene in different species. Generally, in vitro metabolite profiles were predictive for in vivo profiles. The contribution of two major hydroxyl metabolites to activity and toxicity of ospemifene is adequately covered by at least some animal species.

Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8.

The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613) previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N = 150). Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ∼60 and ∼50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150 and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions -2762/-2775 bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/ß-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/ß-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype.

Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated.

Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive. Here, 13 drugs with a carboxylic acid moiety were incubated with human liver microsomes to produce acyl glucuronide conjugates for the determination of acyl glucuronide half-lives by acyl migration and with HepaRG cells to monitor the formation of acyl CoA conjugates, their further conjugate metabolites, and trans-acylation products with glutathione. Additionally, in vitro cytotoxicity and mitochondrial toxicity experiments were performed with HepaRG cells to compare the predictability of toxicity. Clearly, longer acyl glucuronide half-lives were observed for safe drugs compared to drugs that can cause IDT. Correlation between half-lives and toxicity classification increased when "relative half-lives," taking into account the formation of isomeric AG-forms due to acyl migration and eliminating the effect of hydrolysis, were used instead of plain disappearance of the initial 1-O-ß-AG-form. Correlation was improved further when a daily dose of the drug was taken into account. CoA and related conjugates were detected primarily for the drugs that have the capability to cause IDT, although some exceptions to this were observed. Cytotoxicity and mitochondrial toxicity did not correlate to drug safety. On the basis of the results, the short relative half-life of the acyl glucuronide (high acyl migration rate), high daily dose and detection of acyl CoA conjugates, or further metabolites derived from acyl CoA together seem to indicate that carboxylic acid-containing drugs have a higher probability to cause drug-induced liver injury (DILI).