Analysis of glyphosate, aminomethylphosphonic acid, and glufosinate from human urine by HRAM LC-MS.

Aminomethylphosphonic acid (AMPA) is the main metabolite of glyphosate (GLYP) and phosphonic acids in detergents. GLYP is a synthetic herbicide frequently used worldwide alone or together with its analog glufosinate (GLUF). The general public can be exposed to these potentially harmful chemicals; thus, sensitive methods to monitor them in humans are urgently required to evaluate health risks. We attempted to simultaneously detect GLYP, AMPA, and GLUF in human urine by high-resolution accurate-mass liquid chromatography mass spectrometry (HRAM LC-MS) before and after derivatization with 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) or 1-methylimidazole-sulfonyl chloride (ImS-Cl) with several urine pre-treatment and solid phase extraction (SPE) steps. Fmoc-Cl derivatization achieved the best combination of method sensitivity (limit of detection; LOD) and accuracy for all compounds compared to underivatized urine or ImS-Cl-derivatized urine. Before derivatization, the best steps for GLYP involved 0.4 mM ethylenediaminetetraacetic acid (EDTA) pre-treatment followed by SPE pre-cleanup (LOD 37 pg/mL), for AMPA involved no EDTA pre-treatment and no SPE pre-cleanup (LOD 20 pg/mL) or 0.2-0.4 mM EDTA pre-treatment with no SPE pre-cleanup (LOD 19-21 pg/mL), and for GLUF involved 0.4 mM EDTA pre-treatment and no SPE pre-cleanup (LOD 7 pg/mL). However, for these methods, accuracy was sufficient only for AMPA (101-105%), while being modest for GLYP (61%) and GLUF (63%). Different EDTA and SPE treatments prior to Fmoc-Cl derivatization resulted in high sensitivity for all analytes but satisfactory accuracy only for AMPA. Thus, we conclude that our HRAM LC-MS method is suited for urinary AMPA analysis in cross-sectional studies.

Voltammetric determination of adefovir dipivoxil by using a nanocomposite prepared from molecularly imprinted poly(o-phenylenediamine), multi-walled carbon nanotubes and carbon nitride.

An electrochemical sensor for adefovir dipivoxil (ADV) detection was prepared by electropolymerization of o-phenylenediamine in the presence of ADV on a glassy carbon electrode modified with multi-walled carbon nanotubes and carbon nitride. The electrode was characterized by field emission scanning electron microscopy and differential pulse voltammetry. The performance was optimized by response surface methodology. The changes in differential pulse voltammetric peak currents of the redox probe, ferricyanide, were linear to ADV concentrations in the range from 0.1 to 9.9 µmol L-1, with the detection limit of 0.05 µmol L-1 (S/N = 3). The sensor was applied to the determination of ADV in drug formulations, human serum and urine samples. It is selective due to the use of an imprinted material, well reproducible, long-term stable, and regenerable. Graphical abstract By merging the unique properties of carbon nitride with intrinsic properties of MWCNTs, and molecularly imprinted polymers, a novel electrochemical sensor with selective binding sites was prepared for determination of adefovir dipivoxil in pharmaceutical and biological samples.

Validation of reliable and selective methods for direct determination of glyphosate and aminomethylphosphonic acid in milk and urine using LC-MS/MS.

Simple high-throughput procedures were developed for the direct analysis of glyphosate [N-(phosphonomethyl)glycine] and aminomethylphosphonic acid (AMPA) in human and bovine milk and human urine matrices. Samples were extracted with an acidified aqueous solution on a high-speed shaker. Stable isotope labeled internal standards were added with the extraction solvent to ensure accurate tracking and quantitation. An additional cleanup procedure using partitioning with methylene chloride was required for milk matrices to minimize the presence of matrix components that can impact the longevity of the analytical column. Both analytes were analyzed directly, without derivatization, by liquid chromatography tandem mass spectrometry using two separate precursor-to-product transitions that ensure and confirm the accuracy of the measured results. Method performance was evaluated during validation through a series of assessments that included linearity, accuracy, precision, selectivity, ionization effects and carryover. Limits of quantitation (LOQ) were determined to be 0.1 and 10 µg/L (ppb) for urine and milk, respectively, for both glyphosate and AMPA. Mean recoveries for all matrices were within 89-107% at three separate fortification levels including the LOQ. Precision for replicates was ≤ 7.4% relative standard deviation (RSD) for milk and ≤ 11.4% RSD for urine across all fortification levels. All human and bovine milk samples used for selectivity and ionization effects assessments were free of any detectable levels of glyphosate and AMPA. Some of the human urine samples contained trace levels of glyphosate and AMPA, which were background subtracted for accuracy assessments. Ionization effects testing showed no significant biases from the matrix. A successful independent external validation was conducted using the more complicated milk matrices to demonstrate method transferability.

Water-compatible molecularly imprinted polymer as a sorbent for the selective extraction and purification of adefovir from human serum and urine.

A molecularly imprinted polymer has been synthesized to specifically extract adefovir, an antiviral drug, from serum and urine by dispersive solid-phase extraction before high-performance liquid chromatography with UV analysis. The imprinted polymers were prepared by bulk polymerization by a noncovalent imprinting method that involved the use of adefovir (template molecule) and functional monomer (methacrylic acid) complex prior to polymerization, ethylene glycol dimethacrylate as cross-linker, and chloroform as porogen. Molecular recognition properties, binding capacity, and selectivity of the molecularly imprinted polymers were evaluated and the results show that the obtained polymers have high specific retention and enrichment for adefovir in aqueous medium. The new imprinted polymer was utilized as a molecular sorbent for the separation of adefovir from human serum and urine. The serum and urine extraction of adefovir by the molecularly imprinted polymer followed by high-performance liquid chromatography showed a linear calibration curve in the range of 20-100 µg/L with excellent precisions (2.5 and 2.8% for 50 µg/L), respectively. The limit of detection and limit of quantization were determined in serum (7.62 and 15.1 µg/L), and urine (5.45 and 16 µg/L). The recoveries for serum and urine samples were found to be 88.2-93.5 and 84.3-90.2%, respectively.

Determination of nerve agent metabolites in human urine by isotope-dilution gas chromatography-tandem mass spectrometry after solid phase supported derivatization.

A simple and sensitive method has been developed and validated for determining ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA), isobutyl methylphosphonic acid (iBuMPA), and pinacolyl methylphosphonic acid (PMPA) in human urine using gas chromatography-tandem mass spectrometry (GC-MS/MS) coupled with solid phase derivatization (SPD). These four alkyl methylphosphonic acids (AMPAs) are specific hydrolysis products and biomarkers of exposure to classic organophosphorus (OP) nerve agents VX, sarin, RVX, and soman. The AMPAs in urine samples were directly derivatized with pentafluorobenzyl bromide on a solid support and then extracted by liquid-liquid extraction. The analytes were quantified with isotope-dilution by negative chemical ionization (NCI) GC-MS/MS in a selected reaction monitoring (SRM) mode. This method is highly sensitive, with the limits of detection of 0.02 ng/mL for each compound in a 0.2 mL sample of human urine, and an excellent linearity from 0.1 to 50 ng/mL. It is proven to be very suitable for the qualitative and quantitative analyses of degradation markers of OP nerve agents in biomedical samples.

First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses.

CMX001 is a novel, broad-spectrum lipid antiviral conjugate (LAC) that produces high intracellular levels of the active antiviral agent cidofovir diphosphate (CDV-PP). Study CMX001-102 was a randomized, double-blind, placebo-controlled, parallel group, dose-escalating study in healthy volunteers. The objectives of the study were to evaluate the safety and pharmacokinetic parameters of CMX001 after single and multiple doses. Single doses ranging from 0.25 to 2.0 mg/kg of body weight and multiple doses ranging from 0.1 to 1.0 mg/kg (3 total doses, administered every 6 days) were given orally. Safety was assessed using comprehensive clinical and laboratory evaluations, including enhanced monitoring for potential gastrointestinal (GI) effects using wireless capsule endoscopy (WCE). Serial plasma and pooled urine samples were collected to estimate pharmacokinetic parameters for both CMX001 and cidofovir (CDV). No adverse events occurred that prevented dose escalation. No clinically significant drug-related changes in blood chemistry, hematology, renal function, or intraocular pressure were observed. No CMX001-related gastrointestinal mucosal changes were observed by WCE. CMX001 was absorbed rapidly, with maximum plasma concentrations observed 2 to 3 h postdose. Maximum plasma drug concentration and systemic exposure of CMX001 increased approximately in proportion to dose following single and multiple doses; no significant accumulation of CMX001 or CDV was observed following multiple doses. We conclude that CMX001 is orally bioavailable and well tolerated in healthy volunteers at doses up to 2 mg/kg, approximately 140 mg in a typical adult. This is the first demonstration of the use of phospholipid conjugation technology to achieve plasma drug exposures that are expected to result in activity against multiple double-stranded DNA viruses.

Pharmacokinetic comparison of the maleate and free base formulations of LB80380, a novel nucleotide analog, in healthy male volunteers.

OBJECTIVE: LB80380, a dipivoxil ester prodrug of LB80331, is a novel antiviral agent for the treatment of chronic hepatitis B. The aim of this study was to compare the pharmacokinetic differences after single oral administrations of the free base and maleate formulations of LB80380 in healthy male subjects. METHODS: An open-label, single- dose, randomized-sequence, 2-treatment crossover study was conducted in 32 Korean male volunteers. Subjects received either a combination of 60 and 90 mg tablets of the free base LB80380 formulation or a 183 mg (150 mg as a free base) tablet of the maleate LB80380 formulation. Then, after a 14- day washout period, each subject received the other formulation. Plasma and urine concentrations of LB80331 and LB80317 (active metabolites of LB80380) were measured by validated liquid chromatographytandem mass spectrometry assays. A safety assessment, which included vital signs, adverse events, electrocardiograms and clinical laboratory tests, was performed for each subject. RESULTS: A total of 32 healthy subjects was enrolled, and 26 subjects completed the study. Single oral administrations of LB80380 maleate tablets did not result in clinically significant differences in the safety profile compared to the LB80380 free base tablets. The 90% confidence intervals (CIs) for the geometric mean ratios of Cmax and AUClast for LB80331 of the two treatments (maleate versus free base formulation) were 0.986 - 1.1240 and 0.9848 - 1.0533, respectively. The 90% CIs for the geometric mean ratios of Cmax and AUClast for LB80317 were 0.8379 - 0.9696 and 0.7224 - 0.9196. CONCLUSIONS: In healthy male subjects, the 183 mg LB80380 maleate tablet was pharmacokinetically equivalent to the 60 and 90 mg LB80380 free base tablets.

Influence of Renal Function on the Single-Dose Pharmacokinetics of Besifovir, a Novel Antiviral Agent for theTreatment of Hepatitis B Virus Infection.

Per the well-known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment-naïve and lamivudine-resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open-label, single-dose parallel-group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration-time curves of LB80331 increased by 1.5-, 2.5-, and 4.5-fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8-, 3.2-, and 6.2-fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment.

Sensitive and selective quantification of glyphosate and aminomethylphosphonic acid (AMPA) in urine of the general population by gas chromatography-tandem mass spectrometry.

Glyphosate is the highest volume herbicide used worldwide, and its main biodegradation product is aminomethylphosphonic acid (AMPA), both are listed as priority substances in the Human Biomonitoring for Europe (HBM4EU) initiative which aims at improving policy by filling knowledge gaps by targeted research. The objective of the current study was to advance the sensitivity of an existing gas chromatography-tandem mass spectrometry analytical method to measure environmental population exposures. A 50% lower limit of quantification of 0.05 µg/L was achieved for both analytes by slight modifications in sample work-up, and use of another isotope labelled internal standard. In a pilot study, 41 urine samples from the general German population were analysed, of which glyphosate and AMPA could be quantified in 66% and 90% of the samples respectively, which is sufficient to reliably describe distributions of urinary concentrations in the non-occupationally exposed population.

Glyphosate in Portuguese Adults - A Pilot Study.

BACKGROUND: Glyphosate is a broad-spectrum biocide and the active ingredient in the most widely used herbicides worldwide. Since 2015, when the International Agency for Research on Cancer classified it as a Class 2A carcinogen, global interest in this chemical spiked particularly as regards exposure of the general population. OBJECTIVE: An exploratory glyphosate exposure assessment was conducted among Portuguese adults. METHODS: Self-selected participants provided first morning urine which was tested for glyphosate and its metabolite aminomethylphosphonic acid (AMPA) at two distinct periods of time, by two different laboratories using gas chromatography with tandem mass spectrometry (GC-MS-MS) and high performance liquid chromatography linked to triple quadrupole mass spectrometry (HPLC-MS/MS), respectively. RESULTS: In the first round of testing 28% and 50% presented detectable levels of glyphosate and AMPA respectively, with median values of 0.25 and 0.16 µg/L. Systematically available internal dose values were 8.20E-06 mg/Kg (glyphosate) and 5.04-05 mg/Kg (AMPA). In the second round 73% and 97% presented detectable levels of glyphosate and AMPA respectively with median values of 0.13 and 0.10 µg/L. Systematically available internal dose values were 4.00E-06 mg/Kg (glyphosate) and 3.00E-06 mg/Kg (AMPA). CONCLUSIONS: Glyphosate exposure was detected among Portuguese adults, with percentages of glyphosate and AMPA contaminated urine in both rounds of testing and above values from previous studies in other European countries. Systematically available internal doses values were below EFSA's risk assessment values (ADI or AOEL), and as such, the concentration values measured in this study are not per se a human health problem. Even though there were study limitations, it is the first assessment in Portugal and contributes to the overall knowledge map of glyphosate exposure in Europe.

Urine glyphosate level as a quantitative biomarker of oral exposure.

BACKGROUND: Since the classification of glyphosate as a Group 2A substance "probably carcinogenic to humans" by the IARC in 2015, human health concerns have been raised regarding the exposure of operators, bystanders, and consumers. Urine measurement studies have been conducted, but since toxicokinetic data on glyphosate in humans is lacking, a meaningful interpretation of this data regarding exposure is not possible. OBJECTIVE: This study aims to determine the fraction of glyphosate and AMPA excretion in urine after consuming ordinary food with glyphosate residue, to estimate dietary glyphosate intake. METHODS: Twelve participants consumed a test meal with a known amount of glyphosate residue and a small amount of AMPA. Urinary excretion was examined for the next 48 h. RESULTS: Only 1% of the glyphosate dose was excreted in urine. The urinary data indicated the elimination half-life was 9 h. For AMPA, 23% of the dose was excreted in urine, assuming that no metabolism of glyphosate to AMPA occurred. If all of the excreted AMPA was a glyphosate metabolite, this corresponds to 0.3% of the glyphosate dose on a molar basis. CONCLUSION: This study provides a basis for estimating oral glyphosate intake using urinary biomonitoring data.

Towards establishing indicative values for metabolites of organophosphate ester contaminants in human urine.

In 2015, nine laboratories from Belgium, USA, Canada, China, and Australia participated in an interlaboratory exercise to quantify metabolites of organophosphate ester (OPE) contaminants in pooled human urine. Pooled human urine available as SRM 3673 (Organic contaminants in non-smokers' urine) was obtained from the U.S. National Institute of Standards and Technology and was analyzed for its content of OPE metabolites. Each participating laboratory received 10 mL sample and used its own validated method and standards to report the concentrations of the OPE metabolites of its choice. Four OPE metabolites were consistently measured by most laboratories and they were the following diesters: bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), bis(2-chloroethyl) phosphate (BCEP), and bis(1-chloro-2-propyl) phosphate (BCIPP). Concentrations of other OPE metabolites in SRM 3673 were also reported but are only considered as informative values since they were measured by three laboratories at most. All laboratories used liquid chromatography with tandem mass spectrometry (LC-MS/MS) with or without solid-phase extraction (SPE). This is the first study to report indicative values for OPE metabolites in a human urine Standard Reference Material. It is expected that these indicative values obtained for these four metabolites will be used as quality control to ensure compatibility of results in biomonitoring studies and by other researchers who validate their own methods for the quantification of OPE metabolites in human urine.

Quantification of adefovir and pitavastatin in human plasma and urine by LC-MS/MS: A useful tool for drug-drug interaction studies.

As a tool to be used in transporter-mediated drug-drug interaction studies, a sensitive LC-MS/MS method for the simultaneous quantification of adefovir and pitavastatin in human plasma and adefovir in urine was developed and successfully validated. Plasma samples were processed by protein precipitation using methanol with a subsequent concentrating step. Urine samples were diluted using 0.1% formic acid. Separation was achieved on a Synergy Polar-RP reversed phase column (50 × 4.6 mm, 2.5 µm) in gradient elution using a mobile phase composed of water and 0.1% formic acid and a mixture of methanol and acetonitrile (50:50, v/v) containing 0.1% formic acid at a flow rate of 1.0 mL/min. The linear range covered concentrations from 0.273 to 52.6 ng/mL for adefovir and from 0.539 to 104.2 ng/mL for pitavastatin in human plasma, respectively. The calibration curve for adefovir in urine ranged from 0.104 to 10.0 µg/mL. The weighted linear regression (1/conc2) implied excellent linearity with correlation coefficients ≥0.999.

Determination of glyphosate, glyphosate metabolites, and glufosinate in human serum by gas chromatography-mass spectrometry.

This paper describes an assay for the determination of glyphosate (GLYP), glyphosate metabolites [(aminomethyl) phosphonic acid] (AMPA), and glufosinate (GLUF) in human serum. After protein precipitation using acetonitrile and solid-phase extraction, serum samples were derivatized and analyzed by gas chromatography-mass spectrometry (GC-MS). The assay was linear over a concentration range of 3-100.0 microg/ml for GLYP, AMPA, and GLUF. The overall recoveries for the three compounds were >73%. The intra- and inter-day variations were <15%. Precision and accuracy were 6.4-10.6% and 88.2-103.7%, respectively. The validated method was applied to quantify the GLYP and AMPA content in the serum of a GLYP-poisoned patient. In conclusion, the method was successfully applied for the determination of GLYP and its metabolite AMPA in serum obtained from patient of GLYP-poisoning.

Presence of diphenyl phosphate and aryl-phosphate flame retardants in indoor dust from different microenvironments in Spain and the Netherlands and estimation of human exposure.

Phosphate flame retardants (PFRs) are ubiquitous chemicals in the indoor environment. Diphenyl phosphate (DPHP) is a major metabolite and a common biomarker of aryl-PFRs. Since it is used as a chemical additive and it is a common impurity of aryl-PFRs as well as a degradation product, its presence in indoor dust as an additional source of exposure should not be easily ruled out. In this study, DPHP (and TPHP) are measured in indoor dust in samples collected in Spain and in the Netherlands (n=80). Additionally, the presence of other emerging aryl-PFRs was monitored by target screening. TPHP and DPHP were present in all samples in the ranges 169-142,459ng/g and 106-79,661ng/g, respectively. DPHP concentrations were strongly correlated to the TPHP levels (r=0.90, p<0.01), suggesting that DPHP could be present as degradation product of TPHP or other aryl-PFRs. Estimated exposures for adults and toddlers in Spain to TPHP and DPHP via dust ingestion (country for which the number of samples was higher) were much lower than the estimated reference dose (US EPA) for TPHP. However, other routes of exposure may contribute to the overall internal exposure (diet, dermal contact with dust/consumer products and inhalation of indoor air). The estimated urinary DPHP levels for adults and toddlers in Spain (0.002-0.032ng/mL) as a result of dust ingestion were low in comparison with the reported levels, indicating a low contribution of this source of contamination to the overall DPHP exposure. Other aryl-PFRs, namely cresyl diphenyl phosphate (CDP), resorcinol bis(diphenyl phosphate) (RDP), 2-ethylhexyl diphenyl phosphate (EDPHP), isodecyl diphenyl phosphate (IDP) and bisphenol A bis(diphenyl phosphate) (BDP), were all detected in indoor dust, however, with lower frequency.

Urinary metabolites of organophosphate flame retardants in 0-5-year-old children: Potential exposure risk for inpatients and home-stay infants.

Organophosphate flame retardants (OPFRs) have been commonly observed in indoor dust, food, and drinking water in China, but little is known about their exposure levels or factors leading to exposure in Chinese children. In this study, we measured eight metabolites of OPFRs (mOPFRs) in 227 urine samples collected from 0- to 5-year-old children in China. The high detection rates of mOPFRs (60%-100%) in the collected urine samples demonstrated the widespread exposure of this population to OPFRs. The median concentrations indicated that bis(2-chloroethyl)phosphate (BCEP, 0.85 ng/mL) and diphenyl phosphate (DPHP, 0.27 ng/mL) were the dominant chlorinated mOPFRs and nonchlorinated mOPFRs, respectively. Interestingly, the median urinary levels of bis(1-chloro-2-propyl)phosphate (BCIPP, 6.48 ng/mL) and bis(2-butoxyethyl)phosphate (BBOEP, 0.31 ng/mL) in inpatient infants were one order of magnitude higher (p < 0.01) than those observed in outpatient infants. For home-stay participants, furthermore, infants (0-1 year) had the highest median levels of BCIPP (0.72 ng/mL) and dibutyl phosphate (DBP, 0.14 ng/mL) among the three age groups (i.e., 0-1, >1-3, and >3-5 years), and significantly (p < 0.05) negative age-related relationships were found for both urinary mOPFRs. Two set of data on estimated daily intakes (EDIs) were calculated based on the fraction of OPFR excreted as the corresponding mOPFR (FUE) in human liver microsomes (EDIHLM) and S9 fraction (EDIS9) system, respectively. In general, children have relatively high EDIs of tris(2-chloroethyl)phosphate (TCEP: EDIHLM = 485 ng/kg bw/day, EDIS9 = 261 ng/kg bw/day). Furthermore, 17% or 21% of inpatient infants had EDIs that exceeded the reference dose, whereas this value was reduced to 13% in outpatient infants; and this value decreased with age among all home-stay children (0-5 years). Our results indicated that inpatient and home-stay infants had a higher potential risk of OPFR exposure. To our knowledge, this is the first study to identify the elevated urinary levels of mOPFRs in inpatients.

Glyphosate in German adults - Time trend (2001 to 2015) of human exposure to a widely used herbicide.

The broadband herbicide glyphosate (N-[phosphonomethyl]-glycine) and its main metabolite aminomethylphosphonic acid (AMPA) were analyzed by GC-MS-MS in 24h-urine samples cryo-archived by the German Environmental Specimen Bank (ESB). Samples collected in 2001, 2003, 2005, 2007, 2009, 2011, 2012, 2013, 2014, and 2015 were chosen for this retrospective analysis. All urine samples had been provided by 20 to 29 years old individuals living in Greifswald, a city in north-eastern Germany. Out of the 399 analyzed urine samples, 127 (=31.8%) contained glyphosate concentrations at or above the limit of quantification (LOQ) of 0.1µg/L. For AMPA this was the case for 160 (=40.1%) samples. The fraction of glyphosate levels at or above LOQ peaked in 2012 (57.5%) and 2013 (56.4%) after having discontinuously increased from 10.0% in 2001. Quantification rates were lower again in 2014 and 2015 with 32.5% and 40.0%, respectively. The overall trend for quantifiable AMPA levels was similar. Glyphosate and AMPA concentrations in urine were statistically significantly correlated (spearman rank correlation coefficient=0.506, p≤0.001). Urinary glyphosate and AMPA levels tended to be higher in males. The possible reduction in exposure since 2013 indicated by ESB data may be due to changes in glyphosate application in agricultural practice. The ESB will continue monitoring internal exposures to glyphosate and AMPA for following up the time trend, elucidating inter-individual differences, and contributing to the ongoing debate on the further regulation of glyphosate-based pesticides.

Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment.

BACKGROUND: Tenofovir disoproxil fumarate is the prodrug of the acyclic nucleotide reverse transcriptase inhibitor tenofovir that is indicated for use in the treatment of HIV. Tenofovir is eliminated as unchanged drug in the urine, with a significant component of active tubular secretion. The aim of this study was to evaluate the pharmacokinetics of tenofovir in subjects with renal or hepatic impairment, both of which are common in HIV-infected individuals. PATIENTS AND METHODS: HIV seronegative and otherwise healthy subjects with varying degrees of renal or hepatic function were recruited, and tenofovir pharmacokinetics were evaluated over 48 hours (hepatic impairment study) and 96 hours (renal impairment study) following a single tenofovir disoproxil fumarate 300 mg dose. Subjects with hepatic dysfunction were categorised based upon Child-Pugh-Turcotte score, and subjects with renal impairment were categorised based upon their calculated creatinine clearance (CL(CR)) using the Cockcroft-Gault method. RESULTS: As expected for a renally eliminated drug, subjects with and without hepatic impairment displayed similar tenofovir systemic exposures without evidence of substantial alterations in drug disposition, and therefore no dosage adjustments were warranted in these patients. In contrast, in subjects with renal impairment, two distinct groups were observed: (i) subjects with CL(CR)>/=50 mL/min in whom tenofovir pharmacokinetics were similar to subjects with normal renal function; and (ii) subjects with CL(CR) <50 mL/min (moderate or severe impairment) in which tenofovir renal clearance was substantially reduced and thus drug exposures increased. Subjects with end-stage renal disease (ESRD) demonstrated no extrarenal route of tenofovir elimination. Simulations of once-daily or modified dosing regimens demonstrated the need for tenofovir disoproxil fumarate dose-interval adjustment to prevent unnecessary drug accumulation. In patients with ESRD, high-flux haemodialysis efficiently removed tenofovir, with an elimination rate of 134 mL/min and an extraction coefficient of 54%. CONCLUSION: No tenofovir disoproxil fumarate dose adjustment is warranted in the setting of hepatic impairment. Tenofovir disoproxil fumarate 300 mg every 48 hours in individuals with moderate renal impairment and twice weekly corresponding to every 72-96 hours in those with severe renal impairment is recommended in order to target steady-state tenofovir exposures consistent with those observed in subjects with normal renal function receiving tenofovir disoproxil fumarate 300 mg once daily. For subjects receiving thrice-weekly 4-hour maintenance haemodialysis sessions, tenofovir disoproxil fumarate 300 mg administered every 7 days after a haemodialysis session is recommended. HIV-infected patients with significant end-organ dysfunction should be monitored in accordance with clinical practice, including close management of their viral suppression and clinical chemistries.

Absence of clinically relevant pharmacokinetic interaction between ribavirin and tenofovir in healthy subjects.

This was a 36-day, open-label, fixed-sequence, multiple-dose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of ribavirin. Subjects received a 600-mg once-daily oral dose of ribavirin on days 1 and 22 and 300-mg once-daily oral doses of tenofovir disoproxil fumarate on days 17 through 24. Pharmacokinetic sampling was performed on days 1 through 4 and 22 through 25. Pharmacokinetics of ribavirin was not altered by its coadministration with tenofovir disoproxil fumarate as the point estimates (day 22 [test treatment]/day 1 [reference treatment]), and the 90% confidence interval for maximum observed concentration (0.95; 88.7-101) and area under the plasma concentration-time curve up to time of last measurable concentration (1.12; 106-117) were within the equivalence bounds of 80% to 125%. Tenofovir pharmacokinetics after ribavirin coadministration was similar to that observed in previous studies. These results indicate that coadministration of tenofovir disoproxil fumarate and ribavirin does not result in substantial changes to their individual pharmacokinetic profiles.