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Background: Oral gonadotropin-releasing hormone (GnRH) antagonists are promising agents in the treatment of endometriosis-related pain. Here we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral non-peptide GnRH antagonist in premenopausal women with endometriosis. Methods: In the Phase 1 part of the randomized, double-blinded, placebo-controlled, dose-ascending, Phase 1/2 trial, premenopausal women with endometriosis were randomized (4:1) to receive SHR7280 or placebo treatment for 21 consecutive days. The treatment dose started from 200 mg QD, and then increased to 300 mg QD and 200 mg BID. Safety, PK, and PD parameters were assessed. Results: In total, 30 patients received assigned treatment, 24 with SHR7280 and 6 with placebo. SHR7280 was well tolerated. Adverse events (AEs) were reported in 19 (79.2%, 19/24) patients in the SHR7280 group and 5 (83.3%, 5/6) patients in the placebo group. Most AEs were mild and no severe AEs occurred. SHR7280 showed a rapid absorption, with a time to maximum plasma concentration (Tmax) of 1.0 h, 1.0 h, and 0.8 h for the 200 mg QD, 300 mg QD, and 200 mg BID regimens, respectively. Plasma concentration of SHR7280 was dose dependent. The mean half-life (t1/2) at steady state was 6.9 h, 7.4 h, and 2.8 h, respectively, and little or no accumulation was observed. Pharmacodynamic analysis showed that SHR7280 could effectively suppress estradiol and luteinizing hormone concentrations and prevent progesterone increase in a dose-dependent manner. SHR7280 at doses of 300 mg QD and 200 mg BID could suppress estradiol levels within the desired therapeutic window of 20–50 pg/mL throughout the treatment period. Conclusions: SHR7280 showed favorable safety, PK, and PD profiles in the doses of 200 mg QD, 300 mg QD, and 200 mg BID. The results of this study provide evidence to support the further development of SHR7280 as a GnRH antagonist for the treatment of endometriosis-related pain in the subsequent Phase 2 trial. Trial Registry: Trial registration number: Clinicaltrials.gov, identifier: NCT04417972. Trial registration date: 5 June 2020. [ABSTRACT FROM AUTHOR]

Imidocarb (IMD) is commonly used for treatment of eperythrozoon, babesia, piroplasma and trypanosoma in animals, but there are few studies on its pharmacokinetics in cattle. The purpose of this study was to obtain pharmacokinetic parameters and assess the bioequivalence of subcutaneous injections of two IMD formulations in cattle. Forty-eight healthy cattle, 24 males and 24 females, were randomLy divided into two groups (test group and reference group) with 12 males and 12 females per group. The generic IMD was injected subcutaneously with a single dose of 3.0 mg/kg in the test group. Reference group animals were given one injection of the marketed IMD at the same dosage. The limit of detection (LOD) and limit of quantification (LOQ) for IMD in cattle plasma were 0.05 ng/mL and 0.1 ng/mL, respectively. The recoveries ranged from 88.50% to 92.42%, and the equation of this calibration curve was Y = 13672.1X+187.43. The pharmacokinetics parameters of the test group showed that the maximum concentration of 2257.5±273.62 ng/mL was obtained at 2.14±0.67 h, AUC0-t 14553.95±1946.85 ng·h/mL, AUC∞ 15077.88±1952.19 ng·h/mL, T1/2 31.77±25.75 h, CL/F 0.14±0.02 mL/h/g, and Vz/F 6.53±5.34 mL/g. There was no significant difference in AUC0-t, AUC∞ and Cmax between the test group and the reference group (P>0.05). The 90% confidence interval of AUC0-t, AUC0-∞ and Cmax in the test group was included in 80%–125% AUC0-t, AUC0-∞ and 70%–143% Cmax in the reference group, respectively. Based on these results, the two preparations were found to be bioequivalent. [ABSTRACT FROM AUTHOR]

Abstract: A simple, rapid and accurate liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for quantification of mangiferin in rat plasma. After the addition of the internal standard (IS) paracetamol, plasma samples were pretreated by protein precipitation. Chromatographic separation was carried out on a C18 column by isocratic elution with methanol–acetonitrile–1% acetic acid (40:3:57, v/v/v). The detection was performed on a Sciex API 3000 LC/MS/MS with TurboIonSpray ionization (ESI) inlet in the positive ion MRM mode. Good linearity was achieved over the concentration range of 3.01–601ng/mL. Intra- and inter-day precisions were less than 9.1%, and accuracy ranged from 100.5% to 104.0%. The pharmacokinetic profiles of free mangiferin at three dose levels and mangiferin in Zhimu decoction and Zhimu–Huangbai decoction were studied for the first time in rats by this method. After single intragastric administration of free mangiferin 17.5, 35 and 70mg/kg, C max and AUC increased but non-proportional to the doses. At the same dose level (35mg/kg), C max and AUC of mangiferin in two decoctions were significantly higher than the corresponding values of free mangiferin. [ABSTRACT FROM AUTHOR]

Abstract: A simple, rapid and accurate liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for quantification of dihydroartemisinin (DHA) in human plasma. Following a simple single-step liquid–liquid extraction with ethyl acetate, the analyte was separated on a C18 column by isocratic elution with methanol–water–10mM ammonium acetate (80:10:10, v/v/v), and analyzed by mass spectrometry in the positive ion MRM mode. Good linearity was achieved over a wide range of 1.01–2020ng/mL. Intra- and inter-day precisions were less than 9.0%, and accuracy ranged from 93.0 to 98.2%. The pharmacokinetics of DHA injectable powder was studied for the first time in healthy subjects by this method. After single intravenous infusion of DHA injectable powder 40, 80 and 160mg, the elimination half-life (t 1/2λZ ) was 1.69, 1.88 and 1.92h, respectively; mean C max and AUC increased in proportion to the doses. The pharmacokinetics of DHA fit the linear dynamic feature over the DHA dose range studied. [Copyright &y& Elsevier]

A new rapid ultra‐high‐performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry method was established for the qualitative analysis of absorbed ingredients and metabolites of Zhimu–Huangbai herb pair, which is used to treat type 2 diabetes mellitus. A total of 16 absorbed ingredients and 11 metabolites were identified in normal and type 2 diabetes mellitus rats, respectively. Such findings indicated that the diabetic model had no effect on the type of components in plasma. Seven absorbed ingredients and 11 metabolites were first identified after the oral administration of Zhimu–Huangbai herb pair. Thereafter, ultra‐high‐performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry and liquid chromatography‐API4000+ triple quadrupole mass spectrometer methods were established and validated for pharmacokinetic comparative studies of seven major bioactive components in normal and type 2 diabetes mellitus rats. Partial pharmacokinetic parameters in the plasma of type 2 diabetes mellitus rats were significantly different from those in normal rats. To our knowledge, this is the first comparison of absorbed ingredients and metabolites of Zhimu–Huangbai herb pair, and its use in pharmacokinetic studies between normal and type 2 diabetes mellitus rats. Ultimately, our findings provide insights into the clinical usage of Zhimu–Huangbai herb pair. [ABSTRACT FROM AUTHOR]

A rapid, specific and sensitive liquid chromatography–tandem mass spectrometric (LC–MS/MS) method was developed and validated for the simultaneous determination of strychnine, brucine, strychnine N-oxide and brucine N-oxide in rat plasma. Plasma samples were pretreated via simple protein precipitation with methanol and ephedrine hydrochloride was used as internal standard. Chromatographic separation was carried out on an ZORBAX Eclipse XDB-C 18 column (2.1 × 150 mm, 3.5 μm) by gradient elution with methanol and 10 mM ammonium acetate (adjusted to pH 4.0 with formic acid). The quantification of the analytes was performed by mass spectrometry with TurboIonSpray ionization (ESI) inlet in the positive ion multiple reaction monitoring (MRM) mode. The results showed that the calibration curve was linear in the concentration range of 0.510∼306.3 ng mL −1 for strychnine, brucine and 0.102∼306.0 ng mL −1 for strychnine N-oxide and brucine N-oxide, respectively. The intra- and inter-day precisions were less than 14.9%, and the accuracy ranged from 89.4 to 113% at three QC levels for the 4 analytes. The validated method was successfully applied to the pharmacokinetic study of strychnine, brucine, strychnine N-oxide and brucine N-oxide in rat plasma after oral administration of each monomer and the total alkaloids from Semen Strychni. After single oral administration of the total alkaloids from Semen Strychni at 4 dose levels, C max , AUC 0− t of strychnine and brucine increased and were proportional to the oral doses. In comparative pharmacokinetics studies, no significant difference was found between each monomer and the total strychnos alkaloids on the pharmacokinetic parameters such as C max and AUC. Mean C max and AUC of strychnine and brucine were slight increased in the monomer groups in comparison to the total strychnos alkaloids groups, which suggested that some other alkaloids in the Semen Strychni may decrease the absorption of strychnine and brucine in body. [ABSTRACT FROM AUTHOR]

Abstract: Pharmacokinetics of mequindox (MEQ) and its metabolites were determined in rats after intravenous (i.v.) and oral (p.o.) administration of MEQ at a single dose of 10mgkg−1 bodyweight. After both administrations, MEQ and five of its metabolites were quantified, except M4, whereas M1 and M2 were the predominant ones. The areas under the concentration–time curves (hngmL−1) of MEQ, M1, M2, M3, M5 and M10 after i.v. administration were 7559±495, 6354±2761, 5586±2337, 1034±160, 2370±791 and 1813±622, respectively, whereas after p.o. administration, remained as 2809±40, 4361±3544, 4351±1046, 1444±814, 3864±305 and 1213±569, respectively. The elimination half-lives (h) of these compounds after i.v. administration were 3.48±0.80, 4.20±0.76, 6.25±2.41, 4.77±1.54, 4.69±1.62 and 16.89±5.15, respectively, and were 3.21±0.40, 3.66±1.06, 4.20±1.03, 8.91±5.99, 4.20±2.02 and 20.84±10.85 after p.o. administration, respectively. After p.o. administration, the bioavailability of MEQ was 37.16%. The results showed that MEQ was extensively metabolized in rats and rapidly absorbed after p.o. administration. [Copyright &y& Elsevier]

Abstract: Pharmacokinetics of mequindox and one of its major metabolites (M) was determined in chickens after intravenous (i.v.), intramuscular (i.m.) and oral administration of mequindox at a single dose of 10 (i.v. and i.m.) or 20mg/kg b.w. (oral). Plasma concentration profiles were analyzed by a non-compartmental pharmacokinetic method. Following i.v., i.m. and oral administration, the areas under the plasma concentration–time curve (AUC0–∞) were 0.71±0.15, 0.67±0.21, 0.25±0.10μgh/mL (mequindox) and 37.24±7.98, 36.40±9.16, 86.39±16.01μgh/mL (M), respectively. The terminal elimination half-lives (t 1/2λz) were determined to be 0.15±0.06, 0.21±0.09, 0.49±0.23h (mequindox) and 5.36±0.86, 5.39±0.52, 5.22±0.35h (M), respectively. The bioavailabilities (F) of mequindox were 89.4% and 16.6% for i.m. and oral administration. Steady-state distribution volume (V ss) of 1.20±0.34L/kg and total body clearance (Cl B) of 13.57±2.16L/kgh were determined for mequindox after i.v. dosing. After single i.m. and oral administration, peak plasma concentrations (C max) of 3.04±1.32, 0.36±0.13μg/mL (mequindox) and 3.81±0.92, 5.99±1.16μg/mL (M) were observed at t max of 0.08±0.02, 0.32±0.12h (mequindox) and 0.66±0.19, 6.67±1.03h (M), respectively. The results showed that mequindox was rapidly absorbed after i.m. or p.o. administration and most of mequindox was transformed to metabolites in chickens, with much higher C max s and AUCs of metabolite (M) than those of mequindox in plasma. [Copyright &y& Elsevier]

Abstract: Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae. Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects. Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19–40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4–9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters. Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: Tmax, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; tl/2, 13.0 (4.0), 12.6 (5.8), and 9.4 (1.1) hours; AUC0−t, 3344 (1635), 8389 (5164), and 9361 (2428) ng/mL · h−1; and Cmax , 218.7 (68.6), 435.7 (202.1), and 553.4 (152.8) ng/mL. The plasma glucuronidated genistein concentrations were directly proportional to the administered dose over the range of 50 to 100 mg and increased nonproportionately with the 300-mg dose. No statistically significant differences in pharmacokinetic parameters were found in the fasting group compared with the postprandial group. In the multiple-dose group, the mean (SD) steady-state pharmacokinetic parameters on day 9 were similar to those following a single dose of genistein on day 1 (Tmax, 6.0 [1.0] vs 5.9 [1.5] hours, respectively; tl/2, 9.5 [1.5] vs 9.1 [1.5] hours; AUC0−t, 2830 [1541] vs 2078 [1308] ng/mL · h−1; Cmax, 203.1 [130.9] vs 168.4 [105.7] ng/mL). All AEs were assessed as mild or moderate and resolved without treatment, with the exception of elevated alanine aminotransferase and aspartate aminotransferase activities in one subject that resolved with treatment. Conclusions: The pharmacokinetics of glucuronidated genistein appeared to fit the linear-dose range of genistein 50 to 100 mg, but not the 300-mg dose in these healthy Chinese volunteers. Food consumption did not significantly affect the pharmacokinetic properties. No significant differences were observed in the pharmacokinetic parameters after multiple doses of genistein compared with a single dose, suggesting that the drug did not accumulate after multiple doses. [Copyright &y& Elsevier]