Unstable Middle Phalanx Base Fractures Treated With an Internal Joint Stabilizer: Preliminary Results.

BACKGROUND: Unstable fractures of the base of the middle phalanx are notorious for causing chronic loss of proximal interphalangeal (PIP) joint function, and they remain a challenge for the hand surgeon. We report on a temporary intraoperatively constructed internal joint stabilizer for unstable PIP joint injuries. METHODS: Across 2 institutions, a retrospective chart review was performed for cases with acute presentation of pilon fracture or fracture-dislocation of the base of the middle phalanx which were surgically treated with an internal joint stabilizer. Information collected included time from injury to surgical intervention, time from implantation to device removal, complications, and preoperative and postoperative range of motion. RESULTS: Seven patients met the inclusion criteria with a mean age of 51 (range: 24-72) years and a mean follow-up of 29 (range: 11-72) months. After removal of the fixator, the mean arc of PIP joint motion was 8° to 88° (range: 0°-100°). There were no infections, no hardware loosening or failures, and no revision procedures. CONCLUSION: The current findings are comparable to the results for dynamic external fixators. An internal joint stabilizer for unstable injuries to the base of the middle phalanx provides satisfactory functional outcomes, allows early postoperative motion, and mitigates the routine complications which may arise with external fixation.

Green Sea Turtles (Chelonia mydas) Accumulate Heavy Metals Near a Former Skeet Shooting Range in Kailua, O'ahu, Hawai'i.

The present study determined if green sea turtles (Chelonia mydas) in Kailua Bay, Oahu, in the Hawaiian Islands have elevated blood and scute lead (Pb), arsenic (As), and antimony (Sb) concentrations resulting from lead deposition at a historic skeet shooting range. Blood and scute samples were collected and analyzed for Pb, As, and Sb via inductively coupled plasma-mass spectrometry. Prey, water, and sediment samples were also analyzed. Turtle samples in Kailua Bay (45) have blood Pb concentrations (328 ± 195 ng/g) greater than a reference population (Howick Group of Islands, 29.2 ± 17.1 ng/g). Compared with other green turtle populations, only turtles in Oman, Brazil, and San Diego, CA have blood Pb concentrations greater than turtles in Kailua Bay. The estimated daily exposure of Pb from algae sources in Kailua Bay (0.12 mg/kg/day) was significantly lower than the no observed adverse effect level (100 mg/kg) of red-eared slider turtles. However, the chronic effects of Pb on sea turtles is poorly understood and continued monitoring of this population will increase our understanding of the Pb and As loads of sea turtles in Kailua Bay. Environ Toxicol Chem 2023;42:1109-1123. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

A Lock-and-Kill Anticancer Photoactivated Chemotherapy Agent†.

Photosubstitutionally active ruthenium complexes show high potential as prodrugs for the photoactivated chemotherapy (PACT) treatment of tumors. One of the problems in PACT is that the localization of the ruthenium compound is hard to trace. Here, a ruthenium PACT prodrug, [Ru(3)(biq)(STF-31)](PF6 )2 (where 3 = 3-(([2,2':6',2″-ter- pyridin]-4'-yloxy)propyl-4-(pyren-1-yl)butanoate) and biq = 2,2'-biquinoline), has been prepared, in which a pyrene tracker is attached via an ester bond. The proximity between the fluorophore and the ruthenium center leads to fluorescence quenching. Upon intracellular hydrolysis of the ester linkage, however, the fluorescence of the pyrene moiety is recovered, thus demonstrating prodrug cellular uptake. Further light irradiation of this molecule liberates by photosubstitution STF-31, a known cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, as well as singlet oxygen via excitation of the free pyrene chromophore. The dark and light cytotoxicity of the prodrug, embedded in liposomes, as well as the appearance of blue emission upon uptake, were evaluated in A375 human skin melanoma cells. The cytotoxicity of the liposome-embedded prodrug was indeed increased by light irradiation. This work realizes an in vitro proof-of-concept of the lock-and-kill principle, which may ultimately be used to design strategies aimed at knowing where and when light irradiation should be realized in vivo.

Interfacial Characterization of Ruthenium-Based Amphiphilic Photosensitizers.

Nonreactive surfactant molecules have long been used and characterized for a wide range of applications in industries, life science, and everyday life. Recently, new types of functional amphiphilic molecules have emerged that bear another function, for example, a light-absorbing action, or catalytic properties. However, the surfactant properties of these molecules remain to date essentially unknown. In this context, we investigated here the interfacial activity of photocatalytic surfactants based on a ruthenium(II) tris-bipyridine core, functionalized with two alkyl tails. We realized a systematic characterization of the surfactant properties of these molecules at a water-air interface and studied the effect of the alkyl chain length and of the counterions (hexafluorophosphate or chloride) on these properties. Our data demonstrate that ruthenium surfactants with chloride counteranions form a denser layer at the interface, but their surfactant properties can dramatically deteriorate when the chain length of the alkyl tail increases, leading to simple hydrophobic molecules with poor surfactant properties for the longest chains (C17). These findings pave the way for a better use and understanding of photocatalytic soft interfaces.

Shorter Alkyl Chains Enhance Molecular Diffusion and Electron Transfer Kinetics between Photosensitisers and Catalysts in CO2 -Reducing Photocatalytic Liposomes.

Covalent functionalisation with alkyl tails is a common method for supporting molecular catalysts and photosensitisers onto lipid bilayers, but the influence of the alkyl chain length on the photocatalytic performances of the resulting liposomes is not well understood. In this work, we first prepared a series of rhenium-based CO2 -reduction catalysts [Re(4,4'-(Cn H2n+1 )2 -bpy)(CO)3 Cl] (ReCn ; 4,4'-(Cn H2n+1 )2 -bpy=4,4'-dialkyl-2,2'-bipyridine) and ruthenium-based photosensitisers [Ru(bpy)2 (4,4'-(Cn H2n+1 )2 -bpy)](PF6 )2 (RuCn ) with different alkyl chain lengths (n=0, 9, 12, 15, 17, and 19). We then prepared a series of PEGylated DPPC liposomes containing RuCn and ReCn , hereafter noted Cn , to perform photocatalytic CO2 reduction in the presence of sodium ascorbate. The photocatalytic performance of the Cn liposomes was found to depend on the alkyl tail length, as the turnover number for CO (TON) was inversely correlated to the alkyl chain length, with a more than fivefold higher CO production (TON=14.5) for the C9 liposomes, compared to C19 (TON=2.8). Based on immobilisation efficiency quantification, diffusion kinetics, and time-resolved spectroscopy, we identified the main reason for this trend: two types of membrane-bound RuCn species can be found in the membrane, either deeply buried in the bilayer and diffusing slowly, or less buried with much faster diffusion kinetics. Our data suggest that the higher photocatalytic performance of the C9 system is due to the higher fraction of the more mobile and less buried molecular species, which leads to enhanced electron transfer kinetics between RuC9 and ReC9 .

Roadmap towards solar fuel synthesis at the water interface of liposome membranes.

Artificial photosynthesis has experienced rapid developments aimed at producing photocatalytic systems for the synthesis of chemical energy carriers. Conceptual advances of solar fuel systems have been inspired by improved understanding of natural photosynthesis and its key operational principles: (a) light harvesting, (b) charge separation, (c) directional proton and electron transport between reaction centres and across membranes, (d) water oxidation and (e) proton or CO2 reduction catalysis. Recently, there has been a surge of bio-inspired photosynthetic assemblies that use liposomes as nanocompartments to confine reaction spaces and enable vectorial charge transport across membranes. This approach, already investigated in the 1980s, offers in principle a promising platform for solar fuel synthesis. However, the fundamental principles governing the supramolecular assemblies of lipids and photoactive surfactant-like molecules in membranes, are intricate, and mastering membrane-supported photochemistry requires thorough understanding of the science behind liposomes. In this review, we provide an overview of approaches and considerations to construct a (semi)artificial liposome for solar fuel production. Key features to consider for the use of liposomes in solar fuel synthesis are highlighted, including the understanding of the orientation and binding of different components along the membrane, the controlled electron transport between the reaction centres, and the generation of proton gradients as driving force. Together with a list of experimental techniques for the characterisation of photoactive liposomes, this article provides the reader with a roadmap towards photocatalytic fuel production at the interface of lipid membranes and aqueous media.

Trace Element Concentrations in Blood and Scute Tissues from Wild and Captive Hawaiian Green Sea Turtles (Chelonia mydas).

Sea turtles are exposed to trace elements through water, sediment, and food. Exposure to these elements has been shown to decrease immune function, impair growth, and decrease reproductive output in wildlife. The present study compares trace element concentrations in green turtles in captivity at Sea Life Park Hawaii (n = 6) to wild green turtles in Kapoho Bay, Hawaii, USA (n = 5-7). Blood and scute samples were collected and analyzed for 11 elements via inductively coupled plasma-mass spectrometry (ICP-MS). Selenium was significantly greater (p < 0.05) in the blood of captive turtles compared with wild turtles, whereas V, Ni, and Pb were significantly greater in the blood of wild turtles. In scute, V, Cu, Se, and Cr were significantly greater in captive turtles, whereas As was significantly greater in wild turtles. Pelleted food fed to the captive turtles and representative samples of the wild turtle diet were analyzed via ICP-MS to calculate trophic transfer factors and daily intake values. Wild turtles had greater estimated daily intake than captive turtles for all elements except Cu and Se. Because captive turtles are fed a diet very different from that of their wild counterparts, captive turtles do not represent control or reference samples for chemical exposure studies in wild turtles. No toxic thresholds are known for sea turtles, but rehabilitation and managed care facilities should monitor sea turtle elemental concentrations to ensure the animals' health. Environ Toxicol Chem 2021;40:208-218. © 2020 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Carbon nanotubes affect early growth, flowering time and phytohormones in tomato.

Carbon nanotube (CNT) applications are increasing in consumer products, including agriculture devices, making them an important contaminant to study in the field of plant nanotoxicology. Several studies have observed the uptake and effects of CNTs in plants. However, in other studies differing results were observed on growth and physiology depending on the plant species and type of CNT. This study focused on the effects of CNTs on plant phenotype with growth, time to flowering, fruiting time as endpoints, and physiology, through amino acid and phytohormone content, in tomato after exposure to multiple types of CNTs. Plants grown in CNT-contaminated soil exhibited a delay in early growth and flowering (especially in treatments of 1 mg/kg multi-walled nanotubes (MWNTs), 10 mg/kg MWNTs, and 1 mg/kg MWNTs-COOH). However, CNTs did not affect plant growth or height later in the life cycle. No significant differences in abscisic acid (ABA) and citrulline content were observed between the treated and control plants. However, single-walled nanotube (SWNT) exposure significantly increased salicylic acid (SA) content in tomato. These results suggest that SWNTs may elicit a stress response in tomatoes. Results from this study offer more insight into how plants respond and acclimate to CNTs. These results will lead to a better understanding of CNT impact on plant phenotype and physiology.

Bioaccessibility of antimony and other trace elements from lead shot pellets in a simulated avian gizzard environment.

Many studies have used grit (in the form of lead (Pb) pellets) presence in avian gizzards as an indicator of Pb shot exposure. However, due to nearly complete pellet absorption in gizzards or rapid passage of pellets, the absence of Pb shot presence in a gizzard does not confirm lack of Pb shot exposure. This study provides the basis for an additional technique to identify if elevated tissue Pb concentration is due to Pb shot exposure. Bioaccessibility of Pb and trace elements (Sb, As, and Sn) present in Pb shot were quantified to determine if any of these elements would be useful as a secondary marker of Pb shot exposure. An avian physiologically based extraction test (PBET) was used to determine pellet dissolution rate and bioaccessible concentrations of Pb, Sb, As, and Sn in a simulated gizzard environment. Of the three trace elements, only Sb concentrations (44-302 µg/mL) extracted into the gizzard solution were greater than environmental background levels (US soil average 0.48 µg/g); thus, no natural source likely provides this amount of Sb. Therefore, there is evidence that Sb can be extracted from Pb shot in bird gizzards at detectable concentrations (above natural background). While further studies are needed to delineate the mechanisms of absorption and distribution, this study lends credence to the hypothesis that Sb may be a useful marker of Pb shot exposure in biological tissues, particularly when Pb pellets are not present nor observed in avian tissues.

Evaluation and Management Strategies for Per- and Polyfluoroalkyl Substances (PFASs) in Drinking Water Aquifers: Perspectives from Impacted U.S. Northeast Communities.

BACKGROUND: Multiple Northeast U.S. communities have discovered per- and polyfluoroalkyl substances (PFASs) in drinking water aquifers in excess of health-based regulatory levels or advisories. Regional stakeholders (consultants, regulators, and others) need technical background and tools to mitigate risks associated with exposure to PFAS-affected groundwater. OBJECTIVES: The aim was to identify challenges faced by stakeholders to extend best practices to other regions experiencing PFAS releases and to establish a framework for research strategies and best management practices. METHODS AND APPROACH: Management challenges were identified during stakeholder engagement events connecting attendees with PFAS experts in focus areas, including fate/transport, toxicology, and regulation. Review of the literature provided perspective on challenges in all focus areas. Publicly available data were used to characterize sources of PFAS impacts in groundwater and conduct a geospatial case study of potential source locations relative to drinking water aquifers in Rhode Island. DISCUSSION: Challenges in managing PFAS impacts in drinking water arise from the large number of relevant PFASs, unconsolidated information regarding sources, and limited studies on some PFASs. In particular, there is still considerable uncertainty regarding human health impacts of PFASs. Frameworks sequentially evaluating exposure, persistence, and treatability can prioritize PFASs for evaluation of potential human health impacts. A regional case study illustrates how risk-based, geospatial methods can help address knowledge gaps regarding potential sources of PFASs in drinking water aquifers and evaluate risk of exposure. CONCLUSION: Lessons learned from stakeholder engagement can assist in developing strategies for management of PFASs in other regions. However, current management practices primarily target a subset of PFASs for which in-depth studies are available. Exposure to less-studied, co-occurring PFASs remains largely unaddressed. Frameworks leveraging the current state of science can be applied toward accelerating this process and reducing exposure to total PFASs in drinking water, even as research regarding health effects continues. https://doi.org/10.1289/EHP2727.

Anchored Aluminum Catalyzed Meerwein-Ponndorf-Verley Reduction at the Metal Nodes of Robust MOFs.

Catalytic Meerwein-Ponndorf-Verley reductions of ketones and aldehydes in the presence of isopropyl alcohol were performed at aluminum alkoxide sites that were postsynthetically introduced into robust metal-organic frameworks (MOFs). The aluminum was anchored at the bridging hydroxyl sites inherent in some MOFs. MOFs in the UiO-66/67 family as well as DUT-5 were successfully adapted to this strategy. Incorporation of catalytically active aluminum species greatly enhanced the reactivity of the native MOF at 80 °C in the case of both UiO-66, and was almost solely responsible for catalytic activity in the case of metalated UiO-66 and DUT-5. The site isolation of the catalyst prevented aggregation and complete deactivation of the molecular aluminum catalyst, allowing it to be recovered and recycled in the case of UiO-67. This catalyst also proved to be moderately tolerant to wet isopropyl alcohol.

Trophic Transfer and Accumulation of Multiwalled Carbon Nanotubes in the Presence of Copper Ions in Daphnia magna and Fathead Minnow (Pimephales promelas).

The increase in use of nanomaterials such as multiwalled carbon nanotubes (MWCNTs) presents a need to study their interactions with the environment. Trophic transfer was measured between Daphnia magna and Pimephales promelas (fathead minnow, FHM) exposed to MWCNTs with different outer diameter (OD) sizes (MWCNT1 = 8-15 nm OD and MWCNT2 = 20-30 nm OD) in the presence and absence of copper. Pristine FHM were fed D. magna, previously exposed for 3 d to MWCNT1 or MWCNT2 (0.1 mg/L) and copper (0.01 mg/L), for 7 d. D. magna bioaccumulated less MWCNT1 (0.02 µg/g) than MWCNT2 (0.06 µg/g), whereas FHM accumulated more MWCNT1 (0.81 µg/g) than MWCNT2 (0.04 µg/g). In the presence of copper, MWCNT bioaccumulation showed an opposite trend. Mostly MWCNT1 (0.03 µg/g) bioaccumulated in D. magna, however less MWCNT1 (0.21 µg/g) than MWCNT2 (0.32 µg/g) bioaccumulated in FHM. Bioaccumulation factors were higher for MWCNT1s than MWCNT2. However, an opposite trend was observed when copper was added. Plasma metallothionein-2 was measured among treatments; however concentrations were not statistically different from the control. This study demonstrates that trophic transfer of MWCNTs is possible in the aquatic environment and further exploration with mixtures can strengthen the understanding of MWCNT environmental behavior.

Exposure, Effects and Absorption of Lead in American Woodcock (Scolopax minor): A Review.

Due to long term declines of American Woodcock (Scolopax minor) and widespread distribution of environmentally available lead (Pb) throughout their geographic range, it is important to assess if Pb exposure is a potential contributor to these declines. Woodcock are exposed to Pb through various environmental sources and are known to exhibit relatively high bone-Pb concentrations. Absorption of Pb by birds, and woodcock specifically, is not well understood. Some studies show that interactions among calcium, phosphorus, iron, zinc, and vitamin D levels may play an important role in Pb absorption. Therefore, when future Pb studies are performed for woodcock, and other birds, interactions among these elements should be considered. For example, these interactions are relevant in the acquisition and mobilization of calcium in female birds during egg development and shell calcification. These factors should be considered to understand potential mechanisms of Pb exposure, Pb absorption, and subsequent Pb toxicity to birds in general, and woodcock specifically. This review discusses Pb exposure routes, effects of Pb toxicity, and the distribution of Pb in American woodcock and identifies areas for future research in woodcock and other avian species.

Cadmium Compartmentalization in the Pulmonate Snail Lymnaea stagnalis: Improving Our Understanding of Exposure.

In ecotoxicology, analytical compartmentalization analysis can be used to better understand metal sequestration and detoxification. Metals are typically found in two main compartments, biologically detoxified metal (BDM) and metal sensitive fractions (MSF). The purpose of this study was to analyze the subcellular distribution of cadmium (Cd) in Lymnaea stagnalis. Adult snails were exposed to three concentrations of Cd for 56 days as part of a global ring test for L. stagnalis. At the end of the 56-day exposure, organisms were separated in two sections (viscera and foot). Each section was subsequently divided by differential centrifugation into five total fractions including (metal rich granules, debris, Organelles, heat denatured proteins, and heat stable proteins) followed by Cd analysis. The concentration in each compartment, BDM, MSF, and bioconcentration factors were estimated as well. There was significantly higher bioconcentration of Cd in the viscera section compared with the foot. Cadmium accumulation in all five fractions also increased with increasing exposure concentrations. Cadmium accumulated the most in the heat denatured protein fraction (enzymes) and accumulated the least in the heat stable protein fraction (metallothionein-like proteins). The MSF compartment (~65%) was in higher proportion than the BDM (~30%), but only in the lowest Cd exposure concentration was there a significant difference between these compartments. The results indicated that, in general, there was more Cd accumulated in the metal sensitive fractions, and that the detoxification mechanisms were not efficient enough to avoid toxicity at the two highest concentrations. This study provides evidence that improves our understanding of Cd tissue distribution in freshwater gastropods.

Development of primary standards for mass spectrometry to increase accuracy in quantifying environmental contaminants.

Internal standards are essential in electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS) to correct for systematic error associated with ionization suppression and/or enhancement. A wide array of instrument setups and interfaces has created difficulty in comparing the quantitation of absolute analyte response across laboratories. This communication demonstrates the use of primary standards as operational qualification standards for LC-MS instruments and their comparison with commonly accepted internal standards. In monitoring the performance of internal standards for perfluorinated compounds, potassium hydrogen phthalate (KHP) presented lower inter-day variability in instrument response than a commonly accepted deuterated perfluorinated internal standard (d3-PFOS), with percent relative standard deviations less than or equal to 6%. The inter-day precision of KHP was greater than d3-PFOS over a 28-day monitoring of perfluorooctanesulfonic acid (PFOS), across concentrations ranging from 0 to 100µg/L. The primary standard trometamol (Trizma) performed as well as known internal standards simeton and tris (2-chloroisopropyl) phosphate (TCPP), with intra-day precision of Trizma response as low as 7% RSD on day 28. The inter-day precision of Trizma response was found to be greater than simeton and TCPP, across concentrations of neonicotinoids ranging from 1 to 100µg/L. This study explores the potential of primary standards to be incorporated into LC-MS/MS methodology to improve the quantitative accuracy in environmental contaminant analysis.

Localization of nucleoside transporters in rat epididymis.

The epididymis relies on transporters for the secretion of nucleosides and influence the disposition of nucleoside analogs (NSA). Since these compounds can cross the blood-testis barrier (BTB), it is important to understand if the epididymis reabsorbs NSA drugs. The purpose of this study is to determine the localization of nucleoside transporters expressed within rat epididymis to demonstrate the potential of epididymal reabsorption. Using immunohistochemistry, we determined that equilibrative nucleoside transporter 1 (ENT1) is localized to the basolateral membrane of epithelial cells, ENT2 is expressed in the nucleus of the epithelium and CNT2 is expressed by basal cells. The expression pattern for these transporters suggests that nucleosides are able to access the epithelial cells of the epididymal duct via the blood, but not from the lumen. We did not find any evidence for a transepithelial reabsorption pathway indicating the NSA drugs that cross the BTB remain within the epididymis.

Biophysical Viscosity: Thermodynamic Principles of Per Capita Chemical Potentials in Human Populations.

Dynamic viscosity has been used to describe molecular resistance to flow under an applied force. This study introduces the theory of biophysical viscosity, the resistance of a region to molecular flow under environmental force to define the rates of per capita anthropogenic chemical efflux into the environment. Biophysical viscosity is an important intermediate quantity, in that it can be used to calculate the chemical potentials of single molecules for individuals in a population. Nonhypothetical emission data was combined with chemical potentials of anthropogenic tracers, to demonstrate that thermodynamic quantities can be used as parameters to directly compare energies associated with individual chemical emissions across geographic regions. These results indicate that population density is not the only factor in the determination of population-level chemical efflux and that biophysical viscosity is a useful tool in determining the per capita chemical potentials of anthropogenic chemicals for environmental risk assessment.

Arsenic Uptake by Muskmelon (Cucumis melo) Plants from Contaminated Water.

Arsenic is a carcinogenic element that occurs naturally in the environment. High levels of arsenic are found in water in some parts of the world, including Texas. The aims of this study were to determine the distribution of arsenic in muskmelon (Cucumis melo) plants accumulated from arsenic spiked water and to observe effects on plant biomass. Plants were grown and irrigated using water spiked with variable concentrations of arsenic. Inductively coupled plasma mass spectrometry was used to quantify arsenic in different parts of the plant and fruit. Under all conditions tested in this study, the highest concentrations of arsenic were found in the leaves, soil, and roots. Arsenic in the water had no significant effect on plant biomass. Fruits analyzed in this study had arsenic concentrations of 101 µg/kg or less. Consuming these fruits would result in less arsenic exposure than drinking water at recommended levels.

Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir.

BACKGROUND AND AIMS: Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis. METHODS: Animals received a bolus dose of 7mg/kg (35µCi/kg) [(3)H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate. RESULTS: Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion. CONCLUSIONS: This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.

Biliary Elimination of Pemetrexed Is Dependent on Mrp2 in Rats: Potential Mechanism of Variable Response in Nonalcoholic Steatohepatitis.

Hepatic multidrug resistance-associated protein 2 (MRP2) provides the biliary elimination pathway for many xenobiotics. Disruption of this pathway contributes to retention of these compounds and may ultimately lead to adverse drug reactions. MRP2 mislocalization from the canalicular membrane has been observed in nonalcoholic steatohepatitis (NASH), the late stage of nonalcoholic fatty liver disease, which is characterized by fat accumulation, oxidative stress, inflammation, and fibrosis. MRP2/Mrp2 mislocalization is observed in both human NASH and the rodent methionine and choline-deficient (MCD) diet model, but the extent to which it impacts overall transport capacity of MRP2 is unknown. Pemetrexed is an antifolate chemotherapeutic indicated for non-small cell lung cancer, yet its hepatobiliary elimination pathway has yet to be determined. The purpose of this study was to quantify the loss of Mrp2 function in NASH using an obligate Mrp2 transport substrate. To determine whether pemetrexed is an obligate Mrp2 substrate, its cumulative biliary elimination was compared between wild-type and Mrp2(-/-) rats. No pemetrexed was detected in the bile of Mrp2(-/-) rats, indicating pemetrexed is completely reliant on Mrp2 function for biliary elimination. Comparing the biliary elimination of pemetrexed between MCD and control animals identified a transporter-dependent decrease in biliary excretion of 60% in NASH. This study identifies Mrp2 as the exclusive biliary elimination mechanism for pemetrexed, making it a useful in vivo probe substrate for Mrp2 function, and quantifying the loss of function in NASH. This mechanistic feature may provide useful insight into the impact of NASH on interindividual variability in response to pemetrexed.