Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Systemic availability of lipophilic organic UV filters through dermal sunscreen exposure.

BACKGROUND: Chemical UV filters are common components in sunscreens and cosmetic products and used to protect the skin against harmful effects of sunlight like sunburn. However, the effectiveness of sunscreens in the prevention of skin cancer is in some parts still controversial. Meanwhile, questions about negative effects of the chemical UV filters on human health arise and request an effective risk assessment. Real-life exposure data in humans after application of these products are still rare. Thus, we explored whether and to what extent UV filters are absorbed through the skin into the human body. MATERIAL AND METHODS: Plasma and urine samples from 20 healthy volunteers were collected before, during and after a real-life exposure scenario (1st application: 2 mg/cm2; 2nd and 3rd (after 2 and 4 h): 1 mg/cm2 each) using a commercial sunscreen formulation for one day. These samples were analyzed for their content of the currently prominent UV filters octocrylene and avobenzone as well as 2-cyano-3,3-diphenylacrylic acid (CDAA) as the main octocrylene metabolite by using different liquid chromatography electrospray-ionization tandem mass spectrometric procedures. RESULTS: Following dermal sunscreen exposure, avobenzone, octocrylene and CDAA reached concentrations up to 11 µg/L, 25 µg/L and 1352 µg/L in plasma. In urine detection rates of avobenzone and octocrylene were low while CDAA showed a high detection rate and reached up to 5207 µg/g creatinine. Kinetic models could be fitted for octocrylene and CDAA in plasma and CDAA in urine. Concentration peaks were reached between 10 and 16 h after first application and half-life periods were in the range of 1.5 to 2 days. The lipophilic UV filter octocrylene and its metabolite CDAA showed a much slower elimination than other more hydrophilic UV filters. Concordantly, the metabolite CDAA in particular showed a markedly increased renal excretion over the whole sampling period and indicated high internal exposure to OC. DISCUSSION: Real-life sunscreen usage leads to considerable bioavailability of organic UV filters and their metabolites which is rarely seen for other environmental exposures. A combined monitoring of the parent compound and its metabolites is important to fully address internal exposure to the UV filter in humans. Considering the kinetic profiles a prolonged systemic release due to depot formation in skin and a potential accumulation through multi-day exposure is presumed. High in-vivo loads call for a critical toxicological assessment of the UV filters and their metabolites.

Quantification of prominent organic UV filters and their metabolites in human urine and plasma samples.

Monitoring human exposure to chemical UV filters is essential for an accurate assessment of the health risk caused by the resorbed compounds. We developed different procedures for the determination of the prominent UV filters octocrylene (OC), avobenzone (AVO) and 2-ethylhexyl salicylate (EHS) as well as for two OC and EHS metabolites in human urine and OC, AVO and 2-cyano-3,3-diphenylacrylic acid (CDAA) in plasma samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Since the development of a multi-method for all analytes proved to be difficult, three different procedures were established for the determination of AVO, OC and its metabolite CDAA in urine and plasma as well as for EHS and its metabolite 5-hydroxy-EHS in urine. The methods have been validated with good sensitivity, precision and accuracy. The procedures were satisfactorily applied to the determination of the target compounds in human samples collected from volunteers after sunscreen application. These new analytical procedures can provide information on the internal exposure to the UV filters OC, AVO and EHS, which has been little studied.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Effect of the Molecular Weight of Poly(2-methoxyethyl acrylate) on Interfacial Structure and Blood Compatibility.

The blood-compatible polymer poly(2-methoxyethyl acrylate) (PMEA) is composed of nanometer-scale interfacial structures because of the phase separation of the polymer and water at the PMEA/phosphate-buffered saline (PBS) interface. We synthesized PMEA with four different molecular weights (19, 30, 44, and 183 kg/mol) to investigate the effect of the molecular weight on the interfacial structures and blood compatibility. The amounts of intermediate water and fibrinogen adsorption were not affected by the molecular weight of PMEA. In contrast, the degree of denaturation of adsorbed fibrinogen molecules and platelet adhesion increased as the molecular weight increased. Atomic force microscopy observation revealed that the domain size of the microphase separation structures observed at the PMEA/PBS interfaces drastically (nearly 3 times in the mean area of a domain) changed with the molecular weight. PMEA with a lower molecular weight showed a smaller polymer-rich domain size, as expected on the basis of the microphase separation of polymer-rich and water-rich domains. The small domain size suppressed the aggregation and denaturation of adsorbed fibrinogen molecules because only a few fibrinogen molecules were adsorbed on a domain. Increasing the domain size enhanced the denaturation of adsorbed fibrinogen molecules. Controlling the interfacial structures is crucial for ensuring the blood compatibility of polymer interfaces.

Synthesis and Characterization of pH-Sensitive Genipin Cross-Linked Chitosan/Eudragit® L100 Hydrogel for Metformin Release Study Using Response Surface Methodology.

BACKGROUND: In this study, central composite design was utilized for the optimization of genipin cross-linked chitosan/Eudragit®-L 100 interpenetrating hydrogel network films fabricated through solvent evaporation technique. METHODS: Hydrogel formulations were studied using response surface methodology; regression analysis and the surface plots were used to evaluate the effect of variables on T50% (the time for 50% of drug release) and dynamic swelling with optimum formulation selection. Initial burst release of drug was observed from the formulated hydrogels during the first 2 hours of dissolution at simulated gastric pH 1.2 and then slow release during the next 10 hours in the simulated intestinal fluid at pH 7.4. Different polymer ratios in formulation showed significant influence on T50% and dynamic swelling of hydrogel. The highest T50% was observed at 9.89 hour and dynamic swelling at 7.86 h. RESULT: It was observed that by changing the polymer ratio with cross-linker, release rate of metformin could be modified. Cross-linker also affects drug release rate, i.e. the release rate is decreased with the increase in its concentration. The physical state of hydrogel was investigated by scanning electron microscope. CONCLUSION: It indicated the uniform distribution of drug in hydrogel matrix system. Moreover, the presence of hydrogen and ionic bonds between polymers and crosslinking agent formed interpenetrating hydrogel network, likely responsible for increased value of T50%, as confirmed by FTIR. Acute oral toxicity study was performed to investigate the toxic effect of crosslinking agent and polymer used in formulations.

Formulation and statistical optimization of self-microemulsifying drug delivery system of eprosartan mesylate for improvement of oral bioavailability.

The present investigation is aimed to design a statistically optimized self-microemulsifying drug delivery system (SMEDDS) of eprosartan mesylate (EM). Preliminary screening was carried out to find a suitable combination of various excipients for the formulation. A 3(2) full factorial design was employed to determine the effect of various independent variables on dependent (response) variables. The independent variables studied in the present work were concentration of oil (X 1) and the ratio of S mix (X 2), whereas the dependent variables were emulsification time (s), globule size (nm), polydispersity index (pdi), and zeta potential (mV), and the multiple linear regression analysis (MLRA) was employed to understand the influence of independent variables on dependent variables. Furthermore, a numerical optimization technique using the desirability function was used to develop a new optimized formulation with desired values of dependent variables. The optimized SMEDDS formulation of eprosartan mesylate (EMF-O) by the above method exhibited emulsification time, 118.45 ± 1.64 s; globule size, 196.81 ± 1.29 nm; zeta potential, -9.34 ± 1.2 mV, and polydispersity index, 0.354 ± 0.02. For the in vitro dissolution study, the optimized formulation (EMF-O) and pure drug were separately entrapped in the dialysis bag, and the study indicated higher release of the drug from EMF-O. In vivo pharmacokinetic studies in Wistar rats using PK solver software revealed 2.1-fold increment in oral bioavailability of EM from EMF-O, when compared with plain suspension of pure drug.

An LC-MS/MS method for determination of novel fungicide pyraoxystrobin in rat plasma and tissues: Toxicokinetics and tissue distribution study.

A simple, specific and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of pyraoxystrobin in rat plasma and tissues. Chromatographic separation was achieved on a Zorbax Extend-C18 column (50×2.1mm I. D., 3.5µm), using a gradient mobile phase consisting of acetonitrile and 0.1% aqueous formic acid (v/v) at a flow rate of 0.5mL min(-1). Pyraoxystrobin and picoxystrobin (internal standard) were detected without interference in the selected reaction monitoring (SRM) mode with positive electrospray ionization. Further, the method was validated following FDA guideline. The calibration curves for plasma and tissues were linear over a concentration range of 1.00-200ng mL(-1), with lower limits of quantitation of 1.00ng mL(-1). Mean extraction recoveries in plasma and tissues ranged from 101.4% to 108.2% and from 49.1% to 59.4%, respectively. The intra-day and inter-day precision in plasma and tissues were within 9.9% and 8.9%, and the intra-day and inter-day accuracy ranged from 88.7% to 110.7% and 93.2% to 108.7%, respectively. Finally, the validated method was successfully applied to toxicokinetics and tissue distribution studies after oral administration of pyraoxystrobin to rats.

Mass balance, metabolite profile, and in vitro-in vivo comparison of clearance pathways of deleobuvir, a hepatitis C virus polymerase inhibitor.

The pharmacokinetics, mass balance, and metabolism of deleobuvir, a hepatitis C virus (HCV) polymerase inhibitor, were assessed in healthy subjects following a single oral dose of 800 mg of [(14)C]deleobuvir (100 µCi). The overall recovery of radioactivity was 95.2%, with 95.1% recovered from feces. Deleobuvir had moderate to high clearance, and the half-life of deleobuvir and radioactivity in plasma were ∼ 3 h, indicating that there were no metabolites with half-lives significantly longer than that of the parent. The most frequently reported adverse events (in 6 of 12 subjects) were gastrointestinal disorders. Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing ∼ 20% and 15% of the total drug-related material, respectively. Deleobuvir and CD 6168 were the main components in the fecal samples, each representing ∼ 30 to 35% of the dose. The majority of the remaining radioactivity found in the fecal samples (∼ 21% of the dose) was accounted for by three metabolites in which deleobuvir underwent both alkene reduction and monohydroxylation. In fresh human hepatocytes that form biliary canaliculi in sandwich cultures, the biliary excretion for these excretory metabolites was markedly higher than that for deleobuvir and CD 6168, implying that rapid biliary elimination upon hepatic formation may underlie the absence of these metabolites in circulation. The low in vitro clearance was not predictive of the observed in vivo clearance, likely because major deleobuvir biotransformation occurred by non-CYP450-mediated enzymes that are not well represented in hepatocyte-based in vitro models.

Validation of an LC-MS/MS method for the quantitative determination of a novel fungicide: pyraoxystrobin in rat plasma and its application to a toxicokinetics study.

A simple, sensitive, and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed for determination of pyraoxystrobin in rat plasma and applied to a toxicokinetics study. The separation was performed by gradient elution on a Luna 5 µ C18 (2) 100 Å column (50 × 4.6 mm I.D., 5 µm) with mobile phase: water (0.1 % formic acid, v/v)/acetonitrile (0.1 % formic acid, v/v), followed by quantification with a mass detector in multiple reaction monitoring (MRM) mode using ESI as an interface. The calibration curve was linear over a concentration range of 1.00-200 ng/mL. The recovery for pyraoxystrobin ranged from 101.4 to 108.2 %. The intraday bias and precision ranged from -9.3 to 8.1 % and from 0.7 to 8.4 %, respectively, and the interday bias and precision ranged from -0.3 to 4.0 % and from 4.4 to 7.2 %, respectively. The toxicokinetics of pyraoxystrobin after single 100 and 1,000 mg/kg oral doses were studied in rats.

Pharmacokinetic-pharmacodynamic modeling of the antihypertensive effect of eprosartan in Black and White hypertensive patients.

BACKGROUND AND OBJECTIVE: It is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic-pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated. PATIENTS AND METHODS: Eprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1 ± 7.6 years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling. RESULTS: Eprosartan concentration-time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80 % of the maximum decrease in SBP was observed after 24 days. Interindividual variability in drug response was 65 % and decreased to 14 % when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [-2.6 mm Hg per (ng/ml)]. CONCLUSIONS: The developed pharmacokinetic-pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.

Liquid chromatographic method for the simultaneous determination of eprosartan and hydrochlorothiazide in tablets and human plasma.

A new, specific, and sensitive RP-HPLC method was developed for the simultaneous determination of eprosartan (EPR) and hydrochlorothiazide (HCT). Good chromatographic separation was achieved using a 250 x 4.6 mm id, 5 microm particle size Symmetry C18 column. The mobile phase acetonitrile-0.1 M phosphate buffer (35+65, v/v), pH 4.5, was pumped at a flow rate of 1 mL/min, with UV detection at 275 nm. The method showed good linearity in the ranges of 0.5-50 and 0.1-10 microg/mL, with LOD of 0.06 and 0.02 microg/mL and LOQ of 0.20 and 0.08 microg/mL for EPR and HCT, respectively. The proposed method was successfully applied for the analysis of the studied drugs in their synthetic mixture and co-formulated tablets. The method was further extended to the in vitro and in vivo determination of the two drugs in spiked and real human plasma. Interference likely to be encountered from the co-administered drugs was studied.

Functionalization of cyclo-olefin polymer substrates by plasma oxidation: stable film containing carboxylic acid groups for capturing biorecognition elements.

Many current designs in biomedical diagnostics devices are based on the use of low cost, disposable, easy-to-fabricate chips made of plastic material, typically a cyclo-olefin polymer (COP). Low autofluorescence properties of such material, among others, make it ideal substrate for fluorescence-based applications. Functionalization of this plastic substrate for biomolecule attachment is therefore of great importance and the quality of films produced on such surface have often a significant influence on the performance of the device. In this communication we discuss the surface chemistry and some other characteristics of hydrophilic films, containing carboxylic acid functional groups, formed by plasma oxidation of COP and also films containing cross-linked, polymerized acryclic acid produced by sequential deposition of tetraorthosilicate and acrylic acid by plasma enhanced chemical vapor deposition (PECVD). Immobilization of labeled, single stranded DNA revealed high binding capacity for both coatings. To our best knowledge, this is the first example of direct immobilization of biomolecules on just plasma oxidized COP. Furthermore, more sophisticated treatment of the oxidized plastic substrate by PECVD with other organic precursors increased the binding capacity by some 40% than that of just plasma oxidized COP. The carboxy functionalized surfaces, due to the negative charge of the carboxy groups, showed very positive trends towards increasing the signal to noise ratio when charged biomolecules such as DNA, are used.

Sensitization of ABCB1 overexpressing cells to chemotherapeutic agents by FG020326 via binding to ABCB1 and inhibiting its function.

The effectiveness of chemotherapeutic treatment is usually limited by the overexpression of adenosine triphosphate binding cassette (ABC) transporters, which mediate multidrug resistance (MDR) by acting as efflux pumps to remove chemotherapeutic agents from MDR cancer cells. Thus, the inhibition of ABC transporters may represent a promising strategy to reverse MDR. This study was to characterize the actions of FG020326, a newly synthesized triaryl-substituted imidazole derivative, to reverse MDR in vitro and in vivo. FG020326 significantly potentiated the cytotoxicity of paclitaxel, doxorubicin, and vincristine in the ABCB1 (P-glycoprotein, P-gp) overexpressing cells KBv200 and MCF-7/adr, but not in the ABCB1 negative parental cell lines KB and MCF-7. However, FG020326 did not alter the cytotoxicity of the aforementioned drugs in ABCC1 (MRP1), ABCC4 (MRP4), ABCG2 (BCRP) and LRP overexpressing cell lines, KB-CV60, NIH3T3/MRP4-2, S1-M1-80 and SW1573/2R120, respectively. FG020326, following p.o. administration, was present in concentrations sufficient for reversal of MDR in mice. The co-administration of FG020326 with paclitaxel or vincristine significantly enhanced the antitumor activity of these drugs without significantly increasing toxicity in the mice bearing the KBv200 cell xenografts. In addition, FG020326, at concentrations that reversed MDR, did not significantly affect the activity of CYP3A4 or alter the pharmacokinetic profile of paclitaxel after co-administration with paclitaxel. FG020326 produced a significant concentration-dependent displacement of [3H]azidopine and inhibition of efflux of drug from cells. Furthermore, FG020326 was co-localized with ABCB1 in cell membranes. Hence, FG020326 is characterized as a third generation MDR modulator that holds great promise for the treatment of cancer patients with ABCB1-mediated MDR.

Determination of eprosartan in human plasma and urine by LC/MS/MS.

A protein precipitation, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the determination of eprosartan in human plasma and urine. The solvent system also served as a protein precipitation reagent. The chromatographic separation was achieved on a CAPCELL PAK C18 column (50 mmx2.0 mm, 5 microm, Shiseido). A mobile phase was consisted of 0.5% formic acid in water and 0.5% formic acid in acetonitrile (72:28). Detection was by positive ion electrospray tandem mass spectrometry on a Sciex API3000. The standard curves, which ranged from 5 to 2000 ng/mL in human plasma and from 0.25 to 50 microg/mL in urine, were fitted to a 1/x weighted quadratic regression model. The method proved to be accurate, specific and sensitive enough to be successfully applied to a pharmacokinetic study.

Validation of a solid phase extraction-high performance liquid chromatographic method for the determination of eprosartan in human plasma.

In this work, a solid phase extraction-reversed phase high performance liquid chromatographic (SPE-RP-HPLC) method with photometric detection for monitoring the antihypertensive drug eprosartan has been validated in order to assure good quantitation of eprosartan in plasma samples obtained from patients under cardiovascular treatment. This analytical method was developed by using experimental design and quantitation was accomplished with the internal standard method. No interferences were observed from endogenous compounds of plasma and other drugs which are commonly co-administered in elderly patients. The recoveries of eprosartan from plasma samples, measured at three levels of the linear concentration range (150-4000 ng/mL) were found to be between 93.4 and 102.8%. The intraday and interday precision and accuracy (measured by relative standard deviation, RSD, and relative error, RE, respectively) were always lower than 13% (RSD) and 4% (RE). Stability studies showed that eprosartan stock solutions are stable for at least 3 months when stored at 8 degrees C and plasma samples containing the drug were stable at least during the whole analytical method.

A hybrid computational fluid dynamics and physiologically based pharmacokinetic model for comparison of predicted tissue concentrations of acrylic acid and other vapors in the rat and human nasal cavities following inhalation exposure.

To assist in interspecies dosimetry comparisons for risk assessment of the nasal effects of organic acids, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of inhaled vapors in the rat and human nasal cavity. Application to a specific vapor would involve the incorporation of the chemical-specific reactivity, metabolism, partition coefficients, and diffusivity (in both air and tissue phases) of the vapor. This report describes the structure of the CFD-PBPK model and its application to a representative acidic vapor, acrylic acid, for interspecies tissue concentration comparisons to assist in risk assessment. By using the results from a series of short-term in vivo studies combined with computer modeling, regional nasal tissue dose estimates were developed and comparisons of tissue doses between species were conducted. To make these comparisons, the assumption was made that the susceptibilities of human and rat olfactory epithelium to the cytotoxic effects of organic acids were similar, based on similar histological structure and common mode of action considerations. Interspecies differences in response were therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The results of simulations with the seven-compartment CFD-PBPK model suggested that the olfactory epithelium of the human nasal cavity would be exposed to tissue concentrations of acrylic acid similar to that of the rat nasal cavity when the exposure conditions are the same. Similar analysis of CFD data and CFD-PBPK model simulations with a simpler one-compartment model of the whole nasal cavities of rats and humans provides comparable results to averaging over the compartments of the seven-compartment model. These results indicate that the general structure of the hybrid CFD-PBPK model applied in this assessment would be useful for target tissue dosimetry and interspecies dose comparisons for a wide variety of vapors. Because of its flexibility, this CFD-PBPK model is envisioned to be a platform for the construction of case-specific inhalation dosimetry models to simulate in vivo exposures that do not involve significant histopathological damage to the nasal cavity.

Pharmacokinetics and protein binding of eprosartan in hemodialysis-dependent patients with end-stage renal disease.

STUDY OBJECTIVES: To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values. DESIGN: Open-label, parallel-group, single-dose study. SETTING: Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. PATIENTS: Ten healthy volunteers and nine hemodialysis patients. INTERVENTION: A single oral dose of eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis. MEASUREMENTS AND MAIN RESULTS: Concentrations of eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC(0-t) was increased approximately 60% (95% CI-22, 225) in patients. Total Cmax was similar between groups (PE = 1.01, 95% CI -40, 71). Mean percent fraction unbound (%f(u)) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC(0-t) and unbound Cmax were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI -1, 199) greater, respectively, in patients. After hemodialysis, the mean %f(u) decreased from 3.19-2.01%. Mean recovery of eprosartan in dialysate was 6.8 mg (range 0-23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance. CONCLUSIONS: Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of eprosartan after hemodialysis are unnecessary.

Determination of SK&F 108566 (Teveten) in human plasma by reversed-phase high-performance liquid chromatography.

A sensitive, selective and rugged analytical method was developed for the determination of SK&F 108566 (eprosartan, Teveten) in human plasma. The new method employs a simple solid-phase extraction procedure to isolate the drug and its internal standard (SB-200062) from plasma samples. The assay is based on analysis by reversed-phase high-performance liquid chromatography with ultraviolet absorbance detection. The dynamic range of the assay is from 10.0 to 5000 ng/ml, based on 0.5-ml aliquots of plasma. No interference from the endogenous components of plasma, the anticoagulant, or sample collection devices have been noted. The assay has been fully validated. The mean within-run precision (6.5%), between-run precision (4.0%), accuracy (106%) and recovery (71.8%) of the method were considered acceptable. Additionally, SK&F 108566 was found to be stable in plasma under the storage and sample preparation conditions used. This assay has been successfully employed to provide pharmacokinetic data from clinical trials.

Pharmacokinetics and protein binding of eprosartan in healthy volunteers and in patients with varying degrees of renal impairment.

This was an open-label, parallel group study to compare the pharmacokinetics of multiple oral doses of eprosartan in subjects with normal renal function (Clcr > 80 mL/min; n = 8) and patients with mild (Clcr 60-80 mL/min; n = 8), moderate (Clcr 30-59 mL/min; n = 15), or severe (Clcr < 30 mL/min; n = 3) renal insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6 days and a single dose on day 7. Mean total maximum concentration (Cmax) and area under the concentration-time curve from 0 to 12 hours (AUC0-12) were similar for healthy subjects and those with mild renal impairment, but were an average of 25% to 35% and 51% to 55% greater for patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Mean renal clearance (Clr), which was similar for healthy subjects and patients with mild renal impairment, was decreased an average of 41% and 95% in the groups with moderate and severe renal impairment, respectively, compared with normal subjects. Eprosartan was highly bound to plasma proteins in all groups; however, the unbound fraction was increased approximately two-fold in the group with severe renal impairment. Mean unbound Cmax and AUC0-12 were an average of 53% to 61% and 185% to 210% greater for the patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Headache was the most common adverse experience reported in all subgroups. Eprosartan was safe and well tolerated regardless of degree of renal impairment. Cmax and AUC were increased and renal clearance decreased in patients with moderate to severe renal impairment in comparison to healthy subjects and patients with mild renal impairment. However, based on the moderate renal clearance and known safety profile of eprosartan, it is not necessary to adjust the dose of eprosartan in patients with renal insufficiency.