Drugs and hepatic transporters: A review

The liver is the primary organ for the metabolic degradation of xenobiotics. Transmembrane transport proteins from the ABC and the SLC families mediate the uptake of endogenous compounds and xenobiotics into the hepatocyte as well as their elimination from the cells. Multiple processes are involved. The uptake of xenobiotics in hepatocytes is mediated by organic anion transporting polypeptides (OATPs) and by organic anion and cation transporters (OATs and OCTs). The elimination of drugs and metabolites from the liver cell back to the bloodstream is accomplished mainly by multidrug resistance-associated protein 3 (MRP3) and MRP4, while the elimination towards the biliary canaliculi is mediated by several different transporters (MRP2, BCRP, MDR1 and MATE1). Since bile acids and their salts are toxic detergents for hepatocytes, they have to be eliminated efficiently. This task is accomplished by the bile salt export pump BSEP. Two further transporters, MDR3 and ATP8B1 are involved in the proper constitution of bile. All these transporters can be influenced, mainly inhibited by a number of drugs, but also by metabolites from endogenous compounds such as estrogens. Additionally, rare monogenetic diseases exist which can be explained by absence of function or dysfunction of specific hepatic transporters, such as progressive familial intrahepatic cholestasis type 2 by genetic modifications in BSEP that lead to a loss of transporter function. Functional impairment of other transporters by genetics or by drugs also leads to liver injury, a potentially life-threatening disease that is still not fully understood. Hence, the interplay between drugs and hepatic transporters is multiple, and the knowledge of this interplay helps in understanding the etiology and molecular mechanisms behind some forms of (drug-induced) liver injury

Developing a Model for Quantifying QTc-Prolongation Risk to Enhance Medication Safety Assessment: A Retrospective Analysis

There are currently no established methods to predict quantitatively whether the start of a drug with the potential to prolong the QTc interval poses patients at risk for relevant QTc prolongation. Therefore, this retrospective study aimed to pave the way for the development of models for estimating QTc prolongation in patients newly exposed to medications with QTc-prolonging potential. Data of patients with a documented QTc prolongation after initiation of a QTc-prolonging drug were extracted from hospital charts. Using a standard model-building approach, general linear mixed models were identified as the best models for predicting both the extent of QTc prolongation and its absolute value after the start of a QTc-time-prolonging drug. The cohort consisted of 107 adults with a mean age of 64.2 years. Patients were taking an average of 2.4 drugs associated with QTc prolongation, with amiodarone, propofol, pipamperone, ondansetron, and mirtazapine being the most frequently involved. There was a significant but weak correlation between measured and predicted absolute QTc values under medication (r$^2$ = 0.262, p < 0.05), as well as for QTc prolongation (r$^2$ = 0.238, p < 0.05). As the developed models are based on a relatively small number of subjects, further research is necessary to ensure their applicability and reliability in real-world scenarios. Overall, this research contributes to the understanding of QTc prolongation and its association with medications, providing insight into the development of predictive models. With improvements, these models could potentially aid healthcare professionals in assessing the risk of QTc prolongation before adding a new drug and in making informed decisions in clinical settings

The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity

The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases

Potentially inappropriate prescribing for elderly outpatients in Germany: a retrospective claims data analysis

OBJECTIVE: To quantify the frequency of potentially inappropriate medication (PIM) prescribing for outpatients aged 65 years and older using claims data of a German statutory health insurance. METHODS: Based on the 2002 Beers criteria for PIM use, a retrospective evaluation of drug prescription data in outpatient care was conducted for the years 2003 and 2004 using data from a German statutory health insurance (AOK) in the area of Saxony. The study was limited to those drugs classified as being potentially inappropriate according to the criteria independent of existing medical conditions and without any restrictions concerning dosage or duration of use, because this information was not available from the data. RESULTS: In 2003, 3.3% (408,375) of all 12,513,584 drug prescriptions for patients 65 years and older which were analyzed included a PIM from the Beers list. In 2004, it was 2.9% (297,524) of 10,126,809 (p < 0.001). The most frequently prescribed PIMs were short-acting nifedipine (13.4%), indomethacin (12.3%) and diazepam (11.8%) in 2003, and diazepam (14.6%) followed by indomethacin (13.7%) and doxazosin (10.9%) in 2004. 21.7% (119,482) and 18.2% (98,465) of patients 65 years or older received at least one prescription of a PIM in 2003 and 2004, respectively (p < 0.001). In a multivariate logistic regression model female gender and a higher number of prescribed drugs were significantly associated with an increased frequency of receiving a PIM in both years. CONCLUSIONS: In our study, approximately every 5th older patient was prescribed at least one PIM. For the future an ongoing update of the Beers criteria to further include newer agents and an adaptation to the different situation in European countries is desirable

5-Oxoprolin (Pyroglutaminsäure) Azidose unter Paracetamol - Eine Differentialdiagnose der metabolischen Azidose mit erhöhter Anionenlücke

Zusammenfassung. In seltenen Fällen ist eine metabolische Azidose mit stark erweiterter Anionenlücke bei chronischer Paracetamol Therapie auf eine 5-Oxoprolin (Pyroglutaminsäure) Akkumulation zurück zu führen. Begleitende Risikofaktoren, wie Malnutrition, Alkoholabusus, Nieren- oder Lebererkrankungen, Komedikation mit Flucloxacillin, Vigabatrin, Netilmicin oder Sepsis wurden beschrieben. Eine medikamentös induzierte Inhibition der Glutathion Synthetase oder der 5-Oxoprolinase führt zur 5-Oxoprolinerhöhung in Serum und Urin. Andere häufigere Differentialdiagnosen, wie Laktatazidose, Intoxikationen oder Ketoazidose sollten ausgeschlossen werden. Potentiell auslösende Medikamente sollten gestoppt werden, während 5-Oxoprolinkonzentrationen quantifiziert werden können. Bisher unbekannten oder in der Fachinformation des betreffenden Medikamentes ungenügend erwähnte unerwünschte Arzneimittelwirkungen sollten einem regionalen Pharmacovigilance Zentrum zur Signaldetektion gemeldet werden. 5-Oxoprolin Azidose wird demnächst als potentiell unerwünschte Arzneimittelreaktion in den Schweizer Fachinformationen von Paracetamol aufgenommen. </jats:p

Characterization of ligand-induced thermal stability of the human organic cation transporter 2 (OCT2)

Introduction: The human organic cation transporter 2 (OCT2) is involved in the transport of endogenous quaternary amines and positively charged drugs across the basolateral membrane of proximal tubular cells. In the absence of a structure, the progress in unraveling the molecular basis of OCT2 substrate specificity is hampered by the unique complexity of OCT2 binding pocket, which seemingly contains multiple allosteric binding sites for different substrates. Here, we used the thermal shift assay (TSA) to better understand the thermodynamics governing OCT2 binding to different ligands.Methods: Molecular modelling and in silico docking of different ligands revealed two distinct binding sites at OCT2 outer part of the cleft. The predicted interactions were assessed by cis-inhibition assay using [$^{3}$H]1-methyl-4-phenylpyridinium ([$^{3}$H]MPP$^{+}$) as a model substrate, or by measuring the uptake of radiolabeled ligands in intact cells. Crude membranes from HEK293 cells harboring human OCT2 (OCT2-HEK293) were solubilized in n-Dodecyl-β-D-Maltopyranoside (DDM), incubated with the ligand, heated over a temperature gradient, and then pelleted to remove heat-induced aggregates. The OCT2 in the supernatant was detected by western blot.Results: Among the compounds tested, cis-inhibition and TSA assays showed partly overlapping results. Gentamicin and methotrexate (MTX) did not inhibit [$^{3}$H]MPP$^{+}$ uptake but significantly increased the thermal stabilization of OCT2. Conversely, amiloride completely inhibited [$^{3}$H]MPP$^{+}$ uptake but did not affect OCT2 thermal stabilization. [$^{3}$H]MTX intracellular level was significantly higher in OCT2-HEK293 cells than in wild type cells. The magnitude of the thermal shift (ΔT$_{m}$) did not provide information on the binding. Ligands with similar affinity showed markedly different ΔT$_{m}$, indicating different enthalpic and entropic contributions for similar binding affinities. The ΔT$_{m}$ positively correlated with ligand molecular weight/chemical complexity, which typically has high entropic costs, suggesting that large ΔT$_{m}$ reflect a larger displacement of bound water molecules.Discussion: In conclusion, TSA might represent a viable approach to expand our knowledge on OCT2 binding descriptors

Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice

The polymyxin colistin represents a last-resort antibiotic for multidrug-resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimize long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule-1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a cis-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by Western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to that in control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in ex vivo glucose uptake compared to that in BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Background The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether–lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. Methods This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether–lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. Results Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether–lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether–lumefantrine. Cipargamin was well tolerated with no safety concerns. Conclusions This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin