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Fenarimol (FNL), an organic chlorinated fungicide, is widely used in agriculture for protection from fungal spores and fungi. Despite being an endocrine disruptor, no toxicokinetic data is reported for this fungicide. In the present work, we determined the plasma protein binding, metabolic pathways and toxicokinetics of FNL in rats. In vitro binding of FNL to rat and human plasma proteins was ∼90%, suggesting that FNL is a highly protein bound fungicide. The predicted in vivo hepatic clearance of FNL in rats and humans was estimated to be 36.71 and 14.39 mL/min/kg, respectively, indicating it to be an intermediate clearance compound. Reaction phenotyping assay showed that CYP3A4 mainly contributed to the overall metabolism of FNL. The oral toxicokinetic study of FNL in rats at no observed adverse effect level dose (1 mg/kg) showed maximum plasma concentration (Cmax) of 33.97 ± 4.45 ng/mL at 1 h (Tmax). The AUC0–∞ obtained was 180.18 ± 17.76 h*ng/mL, whereas, the t1/2 was ∼4.74 h. Following intravenous administration, FNL displayed a clearance of 42.48 mL/min/kg which was close to the predicted in vivo hepatic clearance. The absolute oral bioavailability of FNL at 1 mg/kg dose in rats was 45.25%. FNL at 10 mg/kg oral dose exhibited non-linear toxicokinetics with greater than dose-proportional increase in the systemic exposure (AUC0–∞ 8270.53 ± 1798.59 h*ng/mL). [ABSTRACT FROM AUTHOR]

ABSTRACT Lumefantrine has been reported to be mainly bio-transformed by cytochrome P450 isozyme 3A4 to desbutyl-lumefantrine (DLF) in human liver microsomes. Since CYP3A is expressed in a sex specific manner in rats, it could be expected that the pharmacokinetics of lumefantrine would be changed in male rats compared with those in female rats. The pharmacokinetics of lumefantrine and its active metabolite DLF were evaluated after intravenous (0.5 mg/kg) and oral (20 mg/kg) administration of lumefantrine to male and female Sprague-Dawley rats. The quantitative bioanalysis was carried out by the liquid chromatography tandem mass spectrometry method. After intravenous and oral administration of lumefantrine the area under the curve ( AUC) of lumefantrine was significantly higher in female rats than that in male rats, whereas the AUC of DLF was significantly lower in female rats in comparison with male rats. This lower AUC of DLF in female rats could have been due to reduced metabolism of lumefantrine in female rats. The bioavailability (% F) of lumefantrine was 1.66 times higher in male rats than that in female rats. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we are reporting permeability and pharmacokinetics of nobiletin in rat plasma and brain, using a validated reverse phase high performance liquid chromatographic method. Protein precipitation method was used for the extraction of nobiletin and coumarin (IS) from rat plasma and brain tissue. The system was run in isocratic mode with mobile phase consisting of potassium dihydrogen ortho-phosphate (pH 4.5; 0.04mM) and acetonitrile in ratio of 50:50, v/v. The total chromatographic run time was 9.0min. The method was proved to be accurate and precise at linearity range of 0.05–10μg/mL with a correlation coefficient (r) of ≥0.994 in rat plasma and ≥0.995 in rat brain. The intra- and inter-day precision and accuracy values are found to be within the assay variability limits as per the FDA guidelines. Nobiletin was found stable in the battery of stability studies viz., bench-top, auto-sampler, freeze/thaw cycles and long term storage in a freezer at −70±10°C. Maximum concentrations of nobiletin in both plasma and brain were observed at 1h after single oral dosing (50mg/kg). The maximum concentration in plasma and brain were 1.78 and 4.20μg/mL, respectively. The AUC0–t in plasma and brain were 7.49 and 20.66μg·h/mL, respectively. The mean elimination half life (t1/2) in plasma and brain were 1.80 and 11.42h, respectively. The Parallel Artificial Membrane Permeability Assay (PAMPA) permeability of nobiletin was found to be high at both pH 4.0 and 7.0. [Copyright &y& Elsevier]

Hexaconazole (HEX) is an azole fungicide widely used in agricultural practices across various countries and numerous studies have reported the toxic effects of HEX, such as endocrine disruption, immunotoxicity, neurotoxicity and carcinogenicity. Despite its widespread agricultural use and toxic effects, the metabolism of HEX is not completely understood, and information on urinary elimination of HEX or its metabolites is limited. Therefore, in the present study, we aimed to identify HEX metabolites in rat and human liver microsomes followed by their in vivo confirmation using a urinary excretion study in rats to identify potential candidate for exposure biomarkers for human biomonitoring studies. From the in vitro assay, a total of 12 metabolites were observed, where the single oxidation metabolites (M5 and M6) were the most abundant metabolites in both rat and human liver microsomes. The triple oxidation followed by dehydration metabolite, M8 (which could also be hexaconazole acid or hydroxy keto-hexaconazole), and the double oxidation metabolite (M9) were the major metabolites found in rat urine and were detectable in rat urine longer than the parent. These metabolites increased with decreasing concentrations of HEX in the rat urine samples. Therefore, metabolites M8, M9 and M5 could be pursued further as potential biomarkers for assessing and monitoring human exposure to HEX. [Display omitted] • Hexaconazole underwent phase-1 metabolism, oxidation was found to be the major pathway. • A total of 12 metabolites of hexaconazole identified in rat and human liver microsomes using HRMS. • Identified hexaconazole metabolites also confirmed in the rat in vivo urine samples. • The oxidative metabolites (M8.M9 and M5) were suggested as potential chemical biomarkers for hexaconazole. [ABSTRACT FROM AUTHOR]

Benzanthrone (BNZ) is a polycyclic aromatic hydrocarbon found in industrial effluent causing skin, respiratory, gastrointestinal, genitourinary, nervous and hemopoietic toxicity. While its toxicity has been well studied, its metabolism in humans has not been investigated. The aim of this study was to characterize species differences in the in vitro metabolism of BNZ in rat and human liver microsomes and to identify the CYP isoforms involved in its metabolism. Upon incubation in liver microsomes, BNZ was found to be a direct substrate of phase I metabolism in both rat and human, undergoing oxidation and reduction. The K m in rat, 11.62 ± 1.49 μM, was two-fold higher than humans (5.97 ± 0.83 μM) suggesting higher affinity for human CYPs. Further, incubation with human rCYPs, BNZ was found to be substrate of multiple CYPs. The predicted in vivo hepatic clearance was 63.55 and 18.91 mL/min/kg in rat and human, respectively, indicating BNZ to be a high clearance compound. BNZ was found to be a moderate inhibitor of human CYP1A2. BNZ metabolism by multiple CYPs indicates that single enzyme genetic polymorphism is unlikely to have profound effect on the toxicokinetics of BNZ and default uncertainty factor of 3.16 might be sufficient to capture the intraspecies kinetic variability. [ABSTRACT FROM AUTHOR]

• Medicarpin is the active anti-osteoporotic constituent of Butea monosperma. • A sensitive LC-ESI-MS/MS method was validated for quantifying of medicarpin in rat plasma, feces, urine, and tissues. • Excretion and distribution studies were carried out in rats. • These studies are useful to understand tissue accumulation and toxicological implications. Medicarpin, one of the active constituents isolated from the extract of Butea monosperma , has been shown to have various pharmacological activities including potent anti-osteoporotic properties. The aim of this study was to investigate the oral pharmacokinetics, tissue distribution and excretion of medicarpin following single oral dose administration in female rats. Oral pharmacokinetics was explored at 5 and 20 mg/kg while tissue distribution, urinary and fecal excretion were studied following 20 mg/kg oral dose. Medicarpin was quantified in rat plasma, urine, feces and tissue samples using a validated LC–MS/MS method following reverse-phase HPLC separation on RP18 column (4.6 mm × 50 mm, 5.0 μm) using methanol and 10 mM ammonium acetate (pH 4.0) as mobile phase in the ratio of 80:20 (v/v) at a flow rate of 0.8 mL/min. The oral bioavailability of medicarpin was found to be low with low systemic levels. The concentration in tissues was significantly higher than plasma. Highest tissue concentrations were found in the liver followed by bone marrow. Urinary and fecal excretion of medicarpin was < 1 %. In conclusion, medicarpin was found to be highly distributed in body tissues and minimally excreted via urine or feces. [ABSTRACT FROM AUTHOR]

Isoformononetin (methoxy isoflavone) is a potent osteogenic isoflavone abundantly present in Butea monosperma , Pisum sativum , Mung bean , Machaerium villosum , Medicago sativa , and Glycine max. In the current study, an LC–ESI-MS/MS method for the simultaneous evaluation of isoformononetin (IFN), daidzein (DZN) and equol (EQL) was developed and validated in rat plasma using biochanin A as an internal standard. IFN, DZN, and EQL separation was achieved by using acetonitrile and acetic acid (0.1%) in the ratio of 90:10 (% v/v) as mobile phase under isocratic conditions at a flow rate of 0.6 mL/min on Atlantis C 18 (4.6 × 250 mm, 5.0 μm) column. The achieved method was linear within the concentration range of 0.5–500 ng/mL. The method was effectively applied to investigate the permeability, protein binding estimation and pharmacokinetics studies of IFN in rats. The PAMPA permeability of IFN was found to be high at pH 4.0 and 7.0. The protein binding was found to be about 91% of IFN. The oral bioavailability of IFN was found to be poor (21.6%). IFN was found to have a moderate clearance (2.9 L/h/kg) and a large apparent volume of distribution (12.1 L/kg). The plasma half-life (t 1/2) and maximum attainable concentration (C max) of IFN at systemic circulation was found to be 1.9 ± 0.6 h and 269.3 ± 0.4 after oral administration. Unlabelled Image • A rapid simultaneous LC-MS/MS method of isoformononetin, daidzein and equol in rat plasma was developed. • The method was sensitive with 0.5 ng/mL as lower limit of quantification for all analytes. • Comprehensive preclinical in vitro and in vivo pharmacokinetics and permeability studies were investigated for first time. • Absolute bioavailability of isoformononetin was low (21.6%). [ABSTRACT FROM AUTHOR]