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The aim of this study was to determine the pharmacokinetics and bioavailability of tolfenamic acid in goats after intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at 2 mg/kg dose. In this study, eight clinically healthy goats were used. The study comprised four periods, according to a crossover design with at least a 15-day washout period between treatments. Plasma concentrations of tolfenamic acid were determined by HPLC-UV, and the pharmacokinetic parameters were estimated using a non-compartmental method. Following IV administration, terminal elimination half-life, volume of distribution at steady state, and total clearance were 1.60 h, 0.37 L/kg, and 0.27 L/h/kg, respectively. The mean peak plasma concentration following IM, SC, and PO administrations was 1.77, 1.22, and 0.30 μg/ml, respectively. The mean bioavailability following IM, SC, and PO administrations was 64.46, 55.43, and 19.46%, respectively. The PO route, which exhibits both the low plasma concentration and bioavailability, is not recommended in goats. The IV, IM, and SC routes, which show comparable pharmacokinetic profiles, may be proposed for use in goats. However, the multi-dose and pharmacodynamic studies are necessary to establish more accurately its safety and efficacy in the goat.

Purpose In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored. Methods Ten patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations. Results Peritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04). Conclusion In this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments. The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907.

This study aimed to develop one novel meloxicam (MEL) oil suspension for sustained-release and compare the pharmacokinetic characteristics of it with MEL conventional formulation in pigs after a single intramuscular administration. Six healthy pigs were used for the study by a crossover design in two periods with a withdrawal interval of 14 days. Plasma concentrations of MEL were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetic parameters were calculated by noncompartmental methods. The difference was statistically significant (p < .05) between MEL oil suspension and MEL conventional formulation in pharmacokinetic parameters of mean residence time (6.16 ± 4.04) hr versus (2.66 ± 0.55) hr, peak plasma concentration (Cmax ) (0.82 ± 0.12) µg/ml versus (1.12 ± 0.22) µg/ml, time needed to reach Cmax (Tmax ) (2.33 ± 0.82) hr versus (0.59 ± 0.18) hr, and terminal elimination half-life (t1/2λz ) (3.74 ± 2.66) hr versus (1.55 ± 0.37) hr. The mean area under the concentration-time curve (AUC0-∝ ) of MEL oil suspension and MEL conventional formulation was 5.35 and 3.43 hr µg/ml, respectively, with a relative bioavailability of 155.98%. Results of the present study demonstrated that the MEL oil suspension could prolong the effective time of drugs in blood, thereby reducing the frequency of administration on a course of treatment. Therefore, the novel MEL oil suspension seems to be of great value in veterinary clinical application.

The aim of this study was to determine the pharmacokinetics of letrozole and its effect on FSH and LH concentrations after single (IV, IM, SC) and repeated IV doses in anestrous ewes. This study was conducted in experiments 1 and 2 by randomly dividing 24 healthy Akkaraman ewes in anestrus into two equal groups. In experiment 1, the pharmacokinetics of letrozole following single IV, IM, and SC administration at 1 mg/kg dose and its effect of a single IV dose on plasma FSH and LH concentration were determined. In experiment 2, the effect of repeated IV doses of letrozole on FSH and LH concentrations was established. Plasma concentration of letrozole was measured using high-performance liquid chromatography, and pharmacokinetic parameters were calculated by non-compartmental analysis. FSH and LH concentrations were quantified using ELISA. The elimination half-life (t1/2ʎz) for IV, IM, and SC routes were 9.94, 37.29, and 41.07 h, respectively. The IV route for letrozole had a total clearance of 0.11 L/h/kg and a volume of distribution at a steady state of 1.50 L/kg. The peak plasma concentration was 0.11 μg/mL for the IM route and 0.14 μg/mL for the SC routes. The bioavailability was 55.18% for the IM route and 75.34% for the SC route. Letrozole following single and repeated (every 24 h for 3 days) IV administrations at 1 mg/kg dose did not affect LH concentration in anestrous ewes but caused an increase in the FSH concentration. This increase in FSH concentration may create a potential for the use of letrozole in ovarian superstimulation protocols. Favorable pharmacokinetic properties (long t1/2ʎz and good bioavailability) of letrozole for IM and SC routes require further investigation before use in estrus induction or estrus synchronization protocols in sheep.

The pharmacokinetics and bioavailability of tolfenamic acid were determined in geese (Anser cygnoides) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral administrations at 2 mg/kg dose. In this study, eight healthy geese (3.5 ± 0.5 kg) were used. The study was performed in four periods according to a crossover design with a 15-day washout period between two administrations. The plasma concentrations of tolfenamic acid were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated by noncompartmental analysis. The elimination half-life was 1.73, 2.51, 2.34, and 2.31 hr for IV, IM, SC, and oral routes, respectively. The volume of distribution at steady state and total clearance after IV administration were 0.25 L/kg and 0.16 L hr-1 kg-1 , respectively. The peak plasma concentrations of tolfenamic acid after IM, SC, and oral administrations were 4.89, 2.94, and 2.92 μg/ml at 0.25, 0.75, and 1 hr, respectively. The bioavailability was 87.91, 77.87, and 76.03% for the IM, SC, and oral routes, respectively. Tolfenamic acid, which exhibits the good bioavailability and plasma concentration following IM, SC, and oral administrations at 2 mg/kg dose, may be useful in the treatment of inflammatory disease conditions in geese.

A single-dose disposition kinetics for tildipirosin was evaluated in clinically healthy ewes (n = 6) after intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration of a commercial formulation. Tildipirosin concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Plasma concentration-time data was calculated by non-compartmental pharmacokinetic methods. The apparent volume of distribution (Vz) of tildipirosin after IV administration was 5.36 &plusmn, 0.57 L/kg suggesting a wide distribution in tissues and inside the cells. The elimination half-life (t&frac12, &lambda, z) was 17.16 &plusmn, 2.25, 23.90 &plusmn, 6.99 and 43.19 &plusmn, 5.17 h after IV, IM and SC administration, respectively. Following IM administration, tildipirosin was rapidly absorbed (tmax = 0.62 &plusmn, 0.10 h) even to a greater extent than after SC administration. Time to reach peak concentration (tmax) and peak plasma concentrations (Cmax) differed significantly, but both parameters showed a more significant variability after SC than after IM administration. Bioavailabilities after extravascular administration were high (&gt, 70%). Therefore, given general adverse reactions that were not observed in any ewe and favourable pharmacokinetics, tildipirosin could be effective in treating bacterial infections in sheep.

Canagliflozin (CNZ) is the first sodium-glucose co-transporter-2 inhibitor approved for treatment of type 2 diabetes mellitus. In the proposed work, a sensitive, rapid and validated high-performance thin-layer chromatography (HPTLC) method was established for the estimation of CNZ in human plasma for the first time. HPTLC analysis of CNZ and internal standard (sildenafil) was performed on glass coated silica gel 60 F254 HPTLC plates using a binary mixture of chloroform-methanol 9:1 (%, v/v) as the mobile phase. Densitometric detection was done at 295 nm. Retardation factor values were obtained as 0.22 and 0.52 for the CNZ and the IS, respectively. The linearity range of CNZ was obtained as 200-3,200 ng/ml. A simple protein precipitation method was used for the extraction of analyte from plasma using methanol. The proposed HPTLC technique was validated for linearity, accuracy, precision and robustness. The proposed HPTLC technique was successfully utilized for the assessment of pharmacokinetic profile of CNZ in rats after oral administration. After oral administration, the peak plasma concentration of CNZ was obtained as 1458.01 ng/ml in 2 h. The proposed HPTLC method could be applied to the study of the pharmacokinetic profile of pharmaceutical formulations containing CNZ.

To evaluate the potential for ethnicity‐related differences in ataluren pharmacokinetics (PK) and safety, a phase 1 single‐dose study was conducted in 48 healthy (24 Japanese and 24 Caucasian subjects), nonsmoking male volunteers who were equally divided into 3 cohorts of oral doses at 5, 10, and 20 mg/kg. Blood samples were collected until 48 hours postdose. PK results demonstrated rapid absorption of ataluren, with peak plasma levels (Cmax) being attained between 0.875 and 2.5 hours after dosing. The mean Cmax and area under the concentration‐time curve (AUC(0‐last)) increased with each increasing dose level in both Japanese and Caucasian subjects. Although the Cmax was similar across all subjects at each dose regardless of ethnicity, Japanese subjects had a mean AUC(0‐last) approximately 14% to 34% lower than that of Caucasian subjects across the 3 dose levels. This difference was likely due to the higher variability of AUC values in Caucasian subjects and the relatively small study population. In conclusion, similar ataluren PK profiles were observed in healthy Japanese and Caucasian subjects following single oral administration of ataluren at all dose levels.

Ethanamizuril (EZL) is a novel triazine anticoccidial compound that has high anticoccidial activity in chickens. In order to treat coccidiosis rationally in poultry, a detection method was developed for ethanamizuril in broiler plasma, and then the pharmacokinetics studies were performed in broilers after oral administration of different dose levels. Ethanamizuril was administered as single oral doses at low (0.67 mg kg−1 BW), medium (1.33 mg kg−1 BW) and high (6.67 mg kg−1 BW) levels in which the medium dose was that recommended in clinics. Plasma concentrations of ethanamizuril were determined using ultra-high performance liquid chromatography and the data were analyzed with a non-compartmental model. Peak plasma concentrations of ethanamizuril were (2.16±0.57), (3.91±0.71), and (23.71±5.02) mg L−1 at (5.17±1.80), (4.60±2.12), and (4.60±2.12) h, respectively. The terminal elimination half-lives (t1/2λz) for ethanamizuril were (10.84±2.59), (10.66±2.47), and (13.34±3.10) h after oral administration at low, medium and high doses, respectively. The areas under the concentration-time curve (AUC0–t) were (37.68±6.87), (73.19±9.18), and (485.76±125.10) mg L−1 h with mean residence times (MRT0–t) of (14.79±3.03), (15.57±3.69), and (20.22±4.01) h at the 3 dosages, respectively. Ethanamizuril was absorbed rapidly and eliminated slowly. A comparison across the dose range indicated that the time to reach peak plasma concentration (Tmax) values were similar while peak plasma concentration (Cmax) and AUC0–t were positively correlated with increasing dosages. This study of the pharmacokinetics of an ethanamizuril solution in chickens provides a theoretical basis for the rational use in the clinic.

PUFA modulate hypothalamic–pituitary–adrenal (HPA) axis activity and cortisol concentrations and therefore affect physiological stress responses and the regulation of energy balance in the short- and long-term. Especially dietary intake ofn-3 PUFA and a loweredn-6:n-3 ratio are highly encouraged due to beneficial and diminishing effects on basal cortisol secretions. However, the time of such effects to occur and how plasma PUFA patterns affect cortisol concentrations in the short-term was rarely investigated. In order to address this, we supplemented forty male and forty female guinea pigs with diets high in the essential PUFAα-linolenic acid (ALA, 18 : 3n-3) and linoleic acid (LA, 18 : 2n-6) for 20 d. Saliva cortisol concentrations in relation to altering plasma PUFA patterns during this time span were analysed in a repeated measurement design both during basal conditions (individual housing) in 5-d intervals and during stressful social confrontations. We detected very fast plasma PUFA accumulation rates, corresponding to the major dietary PUFA, which resulted in plasma PUFA plateau phases after 10 d. ALA negatively and LA positively affected saliva cortisol concentrations throughout the study. A positive effect of the plasman-6:n-3 ratio on saliva cortisol concentrations was detected during peak plasma PUFA accumulations and social confrontations, while no effects were detected in relation to plasma PUFA plateau phases. These results suggest that the plasman-6:n-3 ratio diminishes HPA axis activity during altered physiological conditions only and highlights the importance of altering plasma PUFA patterns for HPA axis functions and the control of energy balance and physiological stress.

Ethanamizuril is a new triazine compound that displays potent anticoccidial activity against chicken coccidiosis caused by Eimeria tenella. We studied the pharmacokinetics of ethanamizuril in rats and chickens after single oral doses of one, two and three times the minimum effective dose Ethanamizuril was readily absorbed at all three doses and the plasma concentration reached was maximal within 5h and progressively declined over time. The mean peak plasma concentrations (Cmax) and the area under the concentration-time curve (AUC) were both dose-dependent. These results provide pharmacokinetic profiles of ethanamizuril for future preclinical studies and clinical use.

Amino acids from meals peak in the plasma at ~180 minutes postprandial. Conversely, amino acids from rapidly digestible whey protein appear in the plasma within 15 minutes and peak at 60 minutes postprandial. Therefore, we hypothesized that consuming a 20-g whey protein snack 2 hours after a standard mixed-macronutrient, lower protein breakfast (10 g) would result in peak and composite postprandial plasma essential amino acid (EAA) responses that were not different from consuming a 30-g protein breakfast alone. Using a randomized, crossover design, 12 subjects (6 men, 6 women; age: 29 ± 1 y; BMI: 26.0 ± 1.0 kg/m2; mean ± SE) completed three 330-minute trials in which they consumed breakfasts containing (i) 10 g of protein (10-PRO, control), (ii) 30 g of protein (30-PRO), and (iii) 10 g of protein followed by 20 g of whey protein isolate 120 minutes later (10/20-PRO). For both 30-PRO and 10/20-PRO, EAA peaked 180 minutes after breakfast, with greater peak concentrations for 10/20-PRO than 30-PRO (Tukey adjusted, P < .0001). Essential amino acid positive incremental areas under the curve (iAUCpos) over 300 minutes were not different between 30-PRO and 10/20-PRO. Consuming a rapidly digested whey protein snack 2 hours after a slowly digested, lower protein breakfast resulted in a greater peak plasma EAA concentration but comparable plasma EAA availability than consuming a single higher protein breakfast.

Quinocetone (QCT), an antimicrobial growth promoter, is widely used in food-producing animals. However, information about pharmacokinetics (PK) of QCT in ducks still remains unavailable up to now. In this study, QCT and its major metabolites (1-desoxyquinocetone, di-desoxyquinocetone and 3-methyl-quinoxaline-2-carboxylic) in ducks were studied using a simple and sensitive UHPLC-MS/MS assay. Twenty ducks were divided into two groups. (n = 10/group). One group received QCT by oral administration at dose of 40 mg/kg while another group received QCT intravenously at 10 mg/kg. Plasma samples were collected at various time points from 0 to 96 hr. QCT and its major metabolites in duck plasma samples were extracted by 1 ml acetonitrile and detected by UHPLC-MS/MS, with the gradient mobile phase that consisted of 0.1% formic acid in water (A) and acetonitrile (B). A noncompartment analysis was used to calculate the PK parameters. The results showed that following oral dosing, the peak plasma concentration (Cmax ) of QCT was 32.14 ng/ml and the area under the curve (AUCINF_obs) was 233.63 (h ng)/ ml. Following intravenous dosing, the Cmax , AUCINF_obs and Vss_obs were 96.70 ng/ml, 152.34 (h ng)/ ml and 807.00 L/kg, respectively. These data indicated that the QCT was less absorbed in vivo following oral administration, with low bioavailability (38.43%). QCT and its major metabolites such as 1-desoxyquinocetone and 3-methyl-quinoxaline-2-carboxylic were detected at individual time points in individual ducks, while the di-desoxyquinocetone was not detected in all time points in all ducks. This study enriches basic scientific data about pharmacokinetics of QCT in ducks after oral and intravenous administration and will be beneficial for clinical application in ducks.

Levofloxacin pharmacokinetic profiles were evaluated in 6 healthy female rabbits after intravenous (I/V), intramuscular (I/M), or subcutaneous (S/C) administration routes at a single dose of 5 mg/kg in a 3 × 3 cross-over study. Plasma levofloxacin concentrations were detected using a validated Ultra Performance Liquid Chromatography method with a fluorescence detector. Levofloxacin was quantifiable up to 10 h post-drug administration. Mean AUC0-last values of 9.03 ± 2.66, 9.07 ± 1.80, and 9.28 ± 1.56 mg/h*L were obtained via I/V, I/M, and S/C, respectively. Plasma clearance was 0.6 mL/g*h after I/V administration. Peak plasma concentrations using the I/M and S/C routes were 3.33 ± 0.39 and 2.91 ± 0.56 μg/mL. Bioavailability values, after extravascular administration were complete, - 105% ± 27% (I/M) and 118% ± 40% (S/C). Average extraction ratio of levofloxacin after I/V administration was 7%. Additionally, levofloxacin administration effects on tear production and osmolarity were evaluated. Tear osmolarity decreased within 48 h post-drug administration. All 3 levofloxacin administration routes produced similar pharmacokinetic profiles. The studied dose is unlikely to be effective in rabbits; however, it was calculated that a daily dose of 29 mg/kg appears effective for I/V administration for pathogens with MIC < 0.5 μg/mL.

Background The purpose was to investigate the effect of caffeine (CAF) mouth rinse on peak power (PP), mean power (MP), peak power relative to body mass (rel PP), mean power relative to body mass (rel MP), fatigue index (FI) and anaerobic contribution in the Wingate Test. Methods Ten healthy men (age: 24.8±3.7 years; body mass: 71.0±7.8 kg; height: 170±3 cm; body fat: 17.02±4.9%; VO2max: 44.15±5.5 ml·kg-1·min=) were recruited. A randomized, double-blind, cross-over design was employed. Participants were instructed to complete Wingate Test in the fastest time possible under 2 conditions: CAF (25 ml of mint syrup with 1.2% of CAF, equivalent to 300 mg of CAF) and placebo (PLA) (25 ml of mint syrup without CAF). Results There was no difference at PP (P=0.66), MP (P=0.16), rel PP (P=0.82), rel MP (P=0.18), FI (P=0.19), anaerobic alactic (P=0.71), anaerobic lactic (P=0.25), total energy expenditure (P=0.41) and peak plasma lactate concentration (P=0.57). Conclusions CAF mouth rinse did not increase peak power (PP), mean power (MP), peak power relative to body mass (rel PP), mean power relative to body mass (rel MP), Fatigue Index (FI) nor anaerobic contribution in the Wingate Test.

The determination of alendronate (ALE) in biofluids using a low-cost instrument is potentially useful in preclinical pharmacokinetic studies. This study developed and validated a high-performance liquid chromatography with ultraviolet method for ALE determination in rat plasma using precolumn derivatization with phenyl isothiocyanate (PITC). Inhibiting compounds in the samples were first eliminated using solid-phase extraction. ALE in the sample was subsequently allowed to react with PITC to form a phenylthiocarbamoyl derivative for further analysis. The assay was linear within the concentration range of 0.29–25.0 µg/mL. The precision and accuracy were less than 3.9% and 98.0 ± 3.9%, respectively. The limits of detection and quantification were 0.08 and 0.20 µg/mL, respectively. The method was successfully used to evaluate the pharmacokinetic parameters of ALE in rats following a single oral administration (30.0 mg/kg). The results show that the peak plasma ALE concentration is 0.69 ± 0.18 µg/mL. ...

The herb-derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (p.o.) administration of ribavirin (30 mg/kg) with or without silymarin (40 mg/kg, p.o.), glycyrrhizin (15 mg/kg, intraperitoneal [i.p.]), or oxymatrine (60 mg/kg, p.o.). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration-time curve (AUC0-t ) and the peak plasma concentration (Cmax ) of ribavirin and ribavirin base by 31.2-44.5% and 48.9-50.0%, respectively. Glycyrrhizin significantly decreased the Cmax and AUC0-t of both ribavirin and its metabolite by 35.3-37.6% and 38.6-39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and Cmax . Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the Cmax (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine.

Present study efforts are focusing to develop the flurbiprofen fast dissolving tablets using sublimation method to enhance the dissolution rate. In this study an attempt was made to fasten the drug release from the oral tablets by incorporating the sublimating agents in the presence of crosspovidone as superdisintegrant and studied the effect on dissolution rate when compared to conventional tablets. In the present study, sublimated fast dissolving tablets were prepared by direct compression method. The prepared tablets were characterized for physical parameters and drug release behavior and the best formulation was subjected to pharmacokinetic studies. From in vitro drug release studies, the formulation F2 showed fast drug release of about 99.94±0.26% in 30 min, and disintegration time 34.42 ± 0.74 sec. The percent drug release in 15 min (Q15) and initial dissolution rate for formulation F2 was 91.46±1.42%, 6.10%/min. The dissolution efficiency was found to be 53.44 and it is increased by 4.5 fold with F2 sublimated tablets. From the pharmacokinetic evaluation, the conventional tablets producing peak plasma concentration (Cmax) was 9023.68±561.83 ng/ml at 3 h Tmax and F2 sublimated tablets showed Cmax 11126.71±123.56 ng/ml at 2 h Tmax. The area under the curve for the conventional and F2 tablets was 30968.42±541.52 and 42973.66±568.13 ng h/ml. Hence, the development of flurbiprofen fast dissolving tablets by sublimation method is a right way to enhance not only the dissolution rate but also the absorption rate.

The present study was expected to develop colon-specific guar gum compression coated tablets of ketorolac tromethamine (KTM). In this study, the core and compression coated tablets were prepared by direct compression method and evaluated. Samples obtained from in vitro dissolution and in vivo pharmacokinetic studies were analyzed using the HPLC method at 319 nm using UV detector. From the in vitro dissolution studies, the formulation F4 showed 4.92±0.36 % drug release in 5 h and it was progressively expanded to 99.92±0.68 % in 24 h. From the pharmacokinetic evaluation, the immediate release tablets producing peak plasma concentration (Cmax) was 4524.61 ng/ml at 2 h Tmax and colon targeted tablets demonstrated Cmax=3396.83 ng/ml at 10 h Tmax. The area under the plasma KTM concentration versus time curves for the immediate release and compression coated tablets were 10894.67 and 17647.58 ng-h/ml respectively and the mean resident time was 3.92 and 10.25 h respectively. From the above results, colon ...

Background This study was undertaken to determine if a clinically relevant drug-drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. Methods Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. Results Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. Conclusions We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug-drug interaction.

The main purpose of this study was to evaluate the pharmacokinetics of levosulpiride in humans after single and multiple intramuscular injections. Six males and six females received single dose of either 25 mg or 50 mg levosulpiride, or multiple doses of 25 mg every 12 h for 5 consecutive days. In the single 25 mg study, the mean peak plasma concentration (Cmax) was 441 ng/mL, the mean area under the concentration–time curve from 0 to 36 h (AUC0–36) was 1724 ng h/mL, and the mean elimination half-life (t1/2) was 7.0 h. In the single 50 mg study, the mean Cmax was 823 ng/mL, the mean AUC0–36 was 3748 ng·h/mL, and the mean t1/2 was 6.8 h. After multiple doses of 25 mg levosulpiride, the average plasma concentration (Cav) was 136 ng/mL, the fluctuation index (DF) was 3.60, and the accumulation ratio (R) was 1.2. Levosulpiride injections appeared to be well tolerated by the subjects, and can be used for successive administration., Graphical abstract The single-dose and multiple-dose pharmacokinetics of levosulpiride after intramuscular administrations of levosulpiride injections have been determined in healthy Chinese volunteers.

The present investigation deals with the determination of bioavailability of Rofecoxib solid dispersion compared to pure rofecoxib (RFB). The study of a non-blinded, open-label, crossover design was conducted in six healthy volunteers. Blood samples were collected for 12 h at specified intervals of time after the administration of formulations and analysed by suitable HPLC method. The pharmacokinetic parameters such as maximum plasma concentration (C max ), time to reach (t max ), elimination rate constant (K el ) biological half-life (t 1/2 ), absorption rate constant (K a ) and area under curve (AUC 0-12 and AUC 0- ) were determined. Significant difference in the bioavailability of pure rofecoxib and solid mixture of rofecoxib prepared using hupu gum as carrier has been reported from the studies. The Peak plasma concentrations (C max ) of 8.34 ng/mL at t max of 4 h and C max of 76.84 ng/mL at t max of 3 h were observed for RFB and solid mixture respectively. The results clearly indicated an enhancement in the bioavailability of rofecoxib in solid mixture preparation.

A single-blind, placebo-controlled, parallel-group and multiple oral dose study was conducted in 48 healthy subjects to investigate the pharmacokinetics and safety of multiple oral doses of sesame lignans (sesamin and episesamin). Subjects were randomly divided into two groups. Each subject was administered 50 mg of sesame lignans (sesamin/episesamin=1/1) or placebo once daily for 28 days. The pharmacokinetics of the sesame lignans were investigated using 10 of the 24 subjects in the sesame lignans group. No serious adverse events were observed in this study. Sesamin was absorbed with a peak plasma concentration at 5.0 h. The plasma concentration of the main metabolite, SC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 2.4 h. Episesamin was also absorbed with a peak plasma concentration at 5.0 h and decreased with a terminal half-life of 7.1 h. The plasma concentration of the main metabolite, EC-1, reached a peak at 5.0 h and decreased rapidly with a terminal half-life of 3.4 h. The plasma concentrations of sesamin and episesamin reached a steady state by day 7. Sesame lignans were confirmed to be safe and tolerable in healthy subjects. The results of the pharmacokinetic study demonstrate that no accumulation was observed following multiple 50 mg doses of sesame lignans.

A sensitive and rapid liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of bakkenolide D (BD), which was further applied to assess the pharmacokinetics of BD. In the LC-MS/MS method, the multiple reaction monitoring mode was used and columbianadin was chosen as internal standard. The method was validated over the range of 1–800 ng/mL with a determination coefficient >0.999. The lower limit of quantification was 1 ng/mL in plasma. The intra- and inter-day accuracies for BD were 91–113 and 100–104%, respectively, and the inter-day precision was

This study was to examine the pharmacokinetics of LB30870, a thrombin inhibitor, after IV and oral administration to rats, dogs, and monkeys. In rats and dogs, LB30870 showed linear pharmacokinetics after IV and oral administration. The oral bioavailability (BA) in rats was about 30 % with high inter-subject variability in the time to reach peak plasma concentration (Tmax). Oral absorption of a solution and prototype tablet formulations of LB30870 were tested in dogs. Tmax was 30 min and the BA values were 40.8–43.1 % with solution formulation. BA values after oral administration of the two tablet formulations at the dose of 100 mg/dog were 27.0 and 30.8 %. Tmax were 60 min in the tablet formulation, indicating that the disintegration and dissolution of tablets caused delay in Tmax compared to solution formulation. After IV administration of LB30870 to monkeys, the plasma concentrations decreased bi-exponentially and BA was 15.0 % after oral (20 mg/kg) dosing. In summary, linear pharmacokinetics of LB30870 were observed in both rats and dogs. The differences in BA among species could be due to difference in absorbed fraction and/or the first pass extraction (pre-systemic elimination) of LB30870.

Pharmacokinetics of cyadox (CYX) and its major metabolites in healthy swine was investigated in this paper. 1,4-Bisdesoxycyadox (BDCYX), cyadox-1-monoxide (CYX-1-O) and quinoxaline-2-carboxylic acid (QCA), three main metabolites of cyadox, were synthesized by College of Science, China Agricultural University. Cyadox (CYX) was administered to 8 healthy cross-bread swine intravenously (i.v.) and orally (p. o.) at a dosage of 1 mg kg−1 body weight and 40 mg kg−1 body weight respectively in a randomized crossover design test with 2-wk washout period. A sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method was developed for the determination of cyadox and its major metabolites in plasma. CYX and its major metabolites BDCYX, and CYX-1-O can be detected after intravenous administration of cyadox while CYX and its metabolites BDCYX, CYX-1-O and QCA can be detected after oral administration of CYX. Plasma concentration vs. time profiles of CYX and its major metabolites were analyzed by non-compartmental pharmacokinetic method. Following i.v. administration, the areas under the plasma concentration-time curve (AUC0-∞) were (0.38±0.03) μg mL−1 h (CYX), (0.018±0.002) μg mL−1 h (BDCYX) and (0.17±0.02) μg mL−1 h (CYX-1-O), respectively. The terminal elimination half-lives (t1/2lz) were determined to be (0.93±0.07) h (CYX), (1.45±0.04) h (BDCYX), and (0.92±0.04) h (CYX-1-O), respectively. Steady-state distribution volume (Vss) of (2.14±0.11) L kg−1 and total body clearance (CL) of (2.84±0.19) L h−1 kg−1 were determined for CYX after i.v. dosing. The bioavailability (F) of CYX was 2.85% for oral administration. After single i.v. administration, peak plasma concentrations (Cmax) of (1.08±0.06) μg mL−1 (CYX), (0.0068± 0.0004) μg mL−1 (BDCYX) and (0.25±0.03) μg mL−1 (CYX-1-O) were observed at Tmax of 0.033 h (CYX), 1 h (BDCYX) and 0.033 h (CYX-1-O), respectively. The main pharmacokinetic parameters after p.o. administration were as follows: AUC0-∞ were (0.42±0.04) μg mL−1 h (CYX), (1.38±0.14) μg mL−1 h (BDCYX), (0.59±0.02) μg mL−1 h (CYX-1-O) and (1.48±0.09) μg mL−1 h (QCA), respectively. t1/2lz were (4.77±0.33) h (CYX), (5.77±0.56) h (BDCYX), (4.12±0.28) h (CYX-1-O), and (8.51±0.39) h (QCA), respectively. After p.o. administration, Cmaxs of (0.033±0.002) μg mL−1 (CYX), (0.22±0.03) μg mL−1 (BDCYX), (0.089±0.005) μg mL−1 (CYX-1-O), and (0.17± 0.01) μg mL−1 (QCA) were observed at Tmax of (7.38±0.33) h (CYX), (7.25±0.31) h (BDCYX), (7.38±0.33) h (CYX-1-O), and (7.25±0.31) h (QCA), respectively. The results showed that CYX was slowly absorbed after oral administration and most of CYX was transformed to its metabolites in swine. The area under plasma concentration-time curve (AUC0-∞) of metabolites were higher than that of CYX after p.o. administration, and the elimination half-lives (t1/2lz) of QCA were longer than those of CYX, CYX-1-O, and BDCYX after oral administration.

The residue levels of sulfadimethoxine (SDM) was studied after oral administration to cultured olive flounder, Paralichthys olivaceus at 20±1.0℃. The concentrations of SDM in the plasma and liver were determined by HPLC-UV detector after a single dosage of 400 ㎎/㎏ body weight. The average recoveries of SDM in spiked samples between 2~50 ppm were 92.24~93.62% for plasma and 88.34~91.90% for liver. Limit of detection for SDM was 0.05 ppm by using this method. Samples were taken at 1 h, 6 h, 12 h, 24 h, 48 h, 72 h, 168 h, 240 h, 336 h and 480 h post-dose. The peak plasma and liver concentrations of SDM, which attained at 1 h post-dose, was 402.64±59.66 ㎍/㎖ and 238.18±54 ㎍/g, respectively. Thereafter, it’s elimination from both tissues was considerably faster following process of time. Their concentrations of SDM were not measurable at 480 h post-dose. Based on this results, dosage and withdrawal times for SDM could be used when it is prescribed with SDM in olive flounder.

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 20 mg/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 (AUC(0-∞)) were 0.71±0.15, 0.67±0.21, 0.25±0.10 μg h/mL (mequindox) and 37.24±7.98, 36.40±9.16, 86.39±16.01 μg h/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±0.23 h (mequindox) and 5.36±0.86, 5.39±0.52, 5.22±0.35 h (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±0.34 L/kg and total body clearance (Cl(B)) of 13.57±2.16 L/kg h 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±0.13 μg/mL (mequindox) and 3.81±0.92, 5.99±1.16 μg/mL (M) were observed at t(max) of 0.08±0.02, 0.32±0.12 h (mequindox) and 0.66±0.19, 6.67±1.03 h (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.

Differences in plasma L-glutamine (L-Gln) concentrations from ingestion of different formulations of L-Gln were examined in 8 men (26.8 ± 4.2 years old, 181.1 ± 10.9 cm, 85.8 ± 15.4 kg). Subjects reported to the laboratory on 4 separate occasions and randomly consumed 1 of 4 drinks containing 60 mg/kg of L-Gln; 89 mg/kg of Sustamine (L-alanylglutamine [AlaGln]; Kyowa Hakko Europe GmbH, Düsseldorf, Germany), which contained an equivalent L-Gln dose as consumed in L-Gln); 200 mg/kg of an enzymatically hydrolyzed wheat protein (HWP) with an L-Gln content of 31 mg/kg; or a control that consisted only of water. It was hypothesized that the AlaGln trial would increase plasma glutamine concentrations greater than the other experimental trials. Ingestion of L-Gln, AlaGln, and HWP resulted in significant increases in the plasma L-Gln concentration, peaking at 0.5, 0.5, and 0.75 hours, respectively. The corresponding mean peak increases were 179 ± 61, 284 ± 84, and 134 ± 36 μmol/L, respectively. Concentrations returned to baseline in all subjects by 2 hours after L-Gln and HWP and by 4 hours after AlaGln. Mean areas under the plasma concentration curve, calculated between 0 and 4 hours, were 127 ± 61, 284 ± 154, and 151 ± 63 μmol∙h∙L⁻¹ for L-Gln, AlaGln, and HWP, respectively. When allowance was made for the lower L-Gln dose administered as HWP, the peak plasma concentration and area under the plasma concentration curve were approximately the same as for AlaGln. The results suggest a greater transfer from the gut to plasma of L-Gln when supplied as AlaGln and possibly also as HWP compared with when the same dose was provided as the free amino acid.

Thirty-two Holstein transition cows were used to determine the effects of monensin (Rumensin, Elanco Animal Health, Greenfield, IN; 400 mg/cow daily) on metabolism and feeding behavior. Cows were assigned randomly, based on calving date, to control or monensin treatments (n = 16 per treatment) 21 days before their expected calving date, and cows remained on treatments through 21 days in milk. Feeding behavior and water intake data were collected daily. Blood samples were collected at 8 different time points during the experimental period. Monensin decreased mean and peak plasma ketone concentrations, and also decreased time between meals before and after calving. No effects of monensin supplementation were observed on milk production or other metabolic traits. Furthermore, we observed no treatment effects on disease incidence, although sample size was small for detecting such effects.

The relationship between the peripheral concentrations of estradiol-17β (E(2)) and the preovulatory characteristics of cumulus oocyte complexes (COCs) during superovulation treatment was investigated in Japanese Black cows. A superovulation regimen with FSH treatment in a descending manner was commenced on day 7 (n=3) or day 10 (n=2) of the estrous cycle (day 0=estrus). Peripheral blood was collected to measure E(2) concentrations twice a day throughout the treatment. Ovariectomies were performed at 100 h after the initial FSH treatment in five cows. Every follicle more than 8 mm in diameter was isolated from the ovaries, and cumulus-oocyte complexes (COCs) were gently aspirated. The COCs were then separated into three groups based on the characteristics of the cumulus (compact, expanded and denuded) and subgrouped based on the stage of the nucleus in the oocytes (GV, GVBD). Plasma E(2) concentrations tended to increase gradually and reached the peak level at around 84 h (E(2)-84: n=3) or 96 h (E(2)-96: n=2) after the initial FSH treatment. The ratio of COCs with expanded cumulus was significantly higher in E(2)-84 than in E(2)-96 (P0.01). However, there was no difference in the ratio of oocytes showing GVBD between E(2)-84 and E(2)-96 (P=0.73), and the characteristics of the cumulus did not affect the stage of the nucleus in the oocytes in either groups (compact, expanded and nude; P=0.61, 0.81 and 1.00). It was possible that the time until the peak plasma E(2) concentrations after the FSH treatment could become an indicator for the maturation of follicles and oocytes in preovulatory follicles during superovulation treatment in Japanese Black cows.

Summary Muscle glycogen resynthesis rates were studied in 6 Standardbred geldings that were exercised on a treadmill inclined at 10% slope to deplete muscle glycogen prior to treatments. Each horse completed 15 min at 50% VO2max, 15 min at 70% VO2max, 5 min at 90% VO2max then rested for 30 min. This was followed by 6, 1 min sprints at 100% VO2max with 5 min rest periods between sprints. Muscle biopsies were taken from the middle gluteal muscle at a depth of 8 cm using the same locations in each horse. Samples were taken before, at the end of exercise and 3, 6, 9, 12 and 24 h after treatment. Blood samples were collected before exercise, immediately after exercise, then every 60 min for 8 h after treatment. Thirty min after exercise each horse was treated with either 6 g/kg dextrose i.v. as a 20% solution in an isotonic electrolyte solution at a mean (± s.e.) infusion rate of 1.67 ± 0.05 1/h, or with a solution of equivalent volume of polyionic isotonic fluid (control) at the same infusion rate. Mean pre-exercise and post infusion peak plasma glucose concentrations were 4.9 ± 0.1 and 28.6 ± 2.8 mmol/l and 4.7 ± 0.2 and 6.0 ± 0.5 mmol/l, for treatment and control respectively. Mean pre-exercise and peak insulin concentrations were 0.007 ± 0.002 and 0.123 ± 0.022 μu/l and 0.006 ± 0.001 and 0.012 ± 0.002 μu/l, for treatment and control respectively. There were significant effects of both time and treatment for glucose and insulin (P

Summary Increases in blood [H+] and lactic acid [La−] attend fatigue. We applied Stewart's physiological model of acid-base status and simple regressions to assess the importance of independent variables and [La−] on [H+] during repeated sprints. Eight well-conditioned Arabians performed 9 sprints. Plasma from jugular vein samples was analysed for pH, Pco2, Na+, K+ and Cl−. Plasma [La−] was calculated from blood [La−], plasma [H+] from pH, SID from Na+, K+, Cl− and La−, Atot from pH, Pco2 and SID. Peaks for SID, Pco2 and [H+] were reached at sprint 1, -2 and -3, respectively. At sprint 3, the 5.7 nmol/l peak in [H+] was partitioned into 2.3, 2.7 and 0.7 nmol/l for Atot, Pco2 and SID, respectively. From sprint 3 to sprint 9, increases in Atot and decreases in SID tended to increase [H+] but were counteracted by a steady decrease in Pco2 that determined the progressive decrease in [H+]. Therefore Pco2 was the dominant determinant of [H+] during 9 repeated sprints, and the expected major effect of [La−] was moderated in the SID by opposing increases in [Na+] and [K+]. In the work-adapted phase (sprints 3–9), decreasing [H+] was correlated positively with Pco2 (r = 0.997, P

The third generation cephalosporin cefovecin has been shown to have an exceptionally long elimination half-life in dogs and cats, making it suitable for antibacterial treatment with a 14-day dosing interval in these species. Pharmacokinetic parameters for cefovecin were investigated in juvenile hens and green iguanas, following subcutaneous injections with 10 mg cefovecin/kg bodyweight. Preliminary studies in eight additional species of birds and reptiles were performed and results were compared with the parameters found in hens and green iguanas. The kinetics were characterized by rapid absorption with peak plasma concentration of 6 +/- 2 microg/mL in hens and 35 +/- 12 microg/mL in green iguanas. The mean plasma half-life for cefovecin was 0.9 +/- 0.3 h for hens and 3.9 h in green iguanas. Volume of distribution was 1.6 +/- 0.5 L/kg for hens and 0.3 L/kg for green iguanas and clearance was 1252 +/- 185 mL.h/kg for hens and 53 mL.h/kg for green iguanas. Results from preliminary studies did not differ notably from those seen in hens and green iguanas. Cefovecin is not suitable for the treatment of bacterial infections with a 14-day dosing interval in hens or green iguanas and seems not to be in a number of other bird and retile species either.

The plasma pharmacokinetic characteristics of the chemopreventive isothiocyanate sulforaphane were determined in six human volunteers following single and repeated intake of raw broccoli. Initially, an analytical method utilising LC-MS/MS, capable of determining low levels of sulforaphane in human plasma was developed and validated. The plasma profile of the isothiocyanate best fitted a two-compartment pharmacokinetic model. Sulforaphane was rapidly absorbed with peak plasma levels being attained within 1.5h, and was characterised by a long terminal elimination phase. Repeated intake of broccoli had no impact on the pharmacokinetic behaviour or plasma levels of sulforaphane, and there was no evidence of accumulation.

1. The objective of this study was to investigate the effect of concomitantly administered silymarin on the pharmacokinetics of talinolol, a typical substrate for P-glycoprotein (P-gp), in healthy Chinese volunteers and its association with a multidrug resistance 1 (MDR1) C3435T genetic polymorphism. 2. Eighteen healthy adult men (six MDR1 3435CC homozygotes, six MDR1 3435CT heterozygotes and six MDR1 3435TT homozygotes) were recruited in a two-phase, randomized, single-blind, crossover design. The pharmacokinetics of talinolol were measured after co-administration of placebo or 140 mg silymarin capsules three times daily for 14 days. Concentrations of talinolol in plasma were measured for up to 36 h after drug administration by liquid chromatography-mass spectrometry (HPLC-MS). 3. The peak plasma concentration (C(max)) of talinolol was significantly higher after silymarin administration as compared with placebo (p = 0.007). The area under the plasma concentration-time curve from zero to 36 h (AUC(0-36)) and AUC(0-infinity) of talinolol was increased by 36.2% +/- 33.2% and 36.5% +/- 37.9%, respectively, by silymarin co-administration. The oral clearance (CL/F) of talinolol was decreased by 23.1% +/- 16.6% (p < 0.001) during the silymarin-treated phase. No change in the time to peak concentration (t(max)) and the blood elimination half-life (t(1/2)) of talinolol was observed between the placebo- and silymarin-treated phases. 4. Co-administration of silymarin significantly increased the plasma concentration of talinolol in healthy volunteers.

The purpose of this study was to investigate the comparative pharmacokinetics of difloxacin in male goat kids and lambs. Difloxacin was administered in a crossover as a single dose of 5 mg kg −1 b.wt. by the intravenous (i.v.) and intramuscular (i.m.) routes in kids and lamb. The concentrations of the drug in the plasma were measured using high-performance liquid chromatography (HPLC) with fluorescence detection. Following i.v. injection, the elimination half-life ( t 1/2 β ) in goat kids (3.57 ± 0.39 h) was higher than in lambs (2.63 ± 0.29 h). The apparent volume of distribution ( V dss ) and the total body clearance (Cl tot ) in goat kids were 0.48 ± 0.03 l kg −1 and 0.12 ± 0.01 l kg −1 h −1 , respectively. The corresponding values in lambs were 0.49 ± 0.04 l kg −1 and 0.11 ± 0.01 l kg −1 h −1 , respectively. After i.m. administration, difloxacin reached a peak plasma concentration ( C max ) of 4.95 ± 0.53 and 4.25 ± 0.47 μg ml −1 at a post-injection time ( T max ) of 1.85 ± 0.23 and 1.31 ± 0.2 h in goat kids and lambs, respectively. The mean bioavailability ( F ) in both goat kids and lambs were 97.5 ± 20.61% and 97.1 ± 21.5%, respectively. The in vitro plasma protein binding % of difloxacin were 10.31 and 12.98 for goat kids and lambs, respectively. Using the surrogate marker C max /MIC and AUC 24 /MIC 90 , difloxacin could be effective by the i.m. route at 5 mg kg −1 against isolates with MIC ≤ 0.5 and 0.4 μg ml −1 for goat kids and lambs, respectively, after i.m. dosing.

The aim of this work was to study the pharmacokinetic behaviour and the inhibitory effect on acetylcholinesterase and butyrylcholinesterase activities of chlorpyrifos in male and female cattle after pour-on administration. Determination of cholinesterase activity in plasma and erythrocyte was carried out according to Ellman kinetic method. The mean baseline activities were 9338.39 +/- 1331.61 and 13220.69 +/- 2274.18 to acetylcholinesterase and 624.65 +/- 39.32 and 641.68 +/- 88.08 IU/L to butyrylcholinesterase in females and males, respectively. Acetylcholinesterase was the predominant form of cholinesterase analyzed, with low levels of butyrylcholinesterase. The basal acetylcholinesterase activities of the bulls were significantly greater than those of cows. The inhibitory effect of topical chlorpyrifos administration was lower on butyrylcholinesterase than on acetylcholinesterase. Chlorpyrifos peak plasma concentration (male:10.920 +/- 4.18; female:12.12 +/- 3.88 microg/L) were reached at 11.92 +/- 9.19 and 8.17 +/- 7.67 h in male and female, respectively. The values of area under curve were 185.96 +/- 168.45 and 278.89 +/- 270.00 microg h/L and mean residence time were 13.95 +/- 8.10 and 14.90 +/- 9.80 h in male and female, respectively.

This study compared pharmacokinetic profiles in cattle dosed subcutaneously with two different formulations of enrofloxacin (5% and 10%) at a dose of 5 mg/kg. Plasma concentrations of enrofloxacin and its active metabolite, ciprofloxacin, were determined by a HPLC/u.v. method. The pharmacokinetic parameters of enrofloxacin and its metabolite were similar in both injectable formulations. Enrofloxacin peak plasma concentration (5%: 0.73 +/- 0.32; 10%: 0.60 +/- 0.14 microg/mL) was reached at 1.21 +/- 0.52 and 1.38 +/- 0.52 h to 5 and 10%, respectively. The terminal half-live and area under curve were 2.34 +/- 0.46 and 2.59 +/- 0.46 h, and 3.09 +/- 0.81 and 2.93 +/- 0.58 microg x h/mL, to 5 and 10%, respectively. The AUC/MIC(90) and Cmax/MIC(90) ratios for both formulations exceed the proposed threshold values for optimized efficacy and minimized resistance development whilst treating infections or septicaemia caused by P. multocida and E. coli.

Two studies measured plasma concentrations of bismuth during dosing with tripotassium dicitrato bismuthate (De-Noltab). The first study compared 24 h plasma bismuth concentration and urinary bismuth excretion in six patients who had already received 29-131 days (median 47 days) of treatment with De-Noltab 2 b.d., and six healthy subjects who only received De-Noltab 2 b.d. on the day of study. There was a prompt rise in plasma bismuth concentration after each dose of De-Noltabs. The median 24 h integrated plasma bismuth concentration was similar in both groups, but the median 24 h urinary bismuth excretion was 5.4-fold higher in the patients. The second study compared the plasma bismuth concentrations after the first and third doses of De-Noltab 2 b.d. in 16 healthy subjects. The median peak bismuth concentration occurred 30 min (range 15-105 min) post-dosing. The peak plasma bismuth concentration was greater than 50 ng/ml in 14 of the 16 subjects, and greater than 100 ng/ml in nine of the subjects. There was no significant difference in the median integrated 10-h plasma bismuth concentration after the first or third dose of De-Noltabs. The results of these studies confirm that bismuth is absorbed and sequestrated during dosing with De-Noltabs. Bismuth is absorbed rapidly after oral dosing with De-Noltabs, to produce peak plasma bismuth concentrations hitherto considered to be in the range associated with bismuth neurotoxicity.

Post-puberal castration of calves is a common management practice in beef production systems. The methods and the age at which castration is performed are considered stressful conditions. The effects of both variables on performance and stress response of beef cattle were evaluated. Data of average daily gain and peak plasma cortisol concentration of calves castrated by surgical and rubber banding methods at different ages were analyzed. Castration-associated weight loss was evaluated within the first 30 days post-castration. The weight loss increased quadratically as the age of castration increased (P 6 months. No statistical differences (P > 0.05) were detected in stress response between surgical and rubber banding procedures. However, the fact that the lower stress response of intact cattle was not statistically different (P > 0.05) from banded cattle suggests that rubber banding castration is less stressful than surgical castration.

The effect of famotidine (4 mg/kg, p.o.) on the kinetic profile of co-administered verapamil (20 mg/kg(-1), p.o.) was studied in the rat. Plasma verapamil levels were collected serially for 12 h and measured using sensitive HPLC method. The pharmacokinetic parameters (elimination half-life, area under the plasma concentration-time curve, peak plasma levels and the times to attain these plasma levels) of verapamil were evaluated in the rat. The results indicate that co-administered famotidine did not significantly alter the pharmacokinetic profile of verapamil in the rat. The present finding suggests that famotidine may safely be co-administered with verapamil but clearly further studies in human subjects are needed to reliably rule out the potential interaction of these two drugs.

Aim: To investigate the influence of dosage forms on the pharmacokinetics of daidzein and its main metabolite daidzein- 7-O -glucuronide in Wistar rats. Methods: After administration of two typical dosage forms (daidzein solution and suspension), the concentrations of daidzein and daidzein- 7-O -glucuronide were determined by an LC-MS-MS method. The pharmacokinetic parameters were calculated and analyzed statistically using the Student's t-test . Results: Absorption of daidzein after administration of daidzein solution (t max = 0.46 h) was more rapid than that of the suspension (t max = 5.00 h). The peak plasma concentrations of daidzein after administration of daidzein solution and suspension were 601.1 mug/L and 127.3 mug/L, respectively, and those of daidzein- 7-O -glucuronide were 3000 mug/L and 192.6 mug/L, respectively. The absolute bioavailabilities of free daidzein in rats after administration of daidzein solution and suspension were 12.8% and 6.1%, respectively, which were calculated to be 47.0% and 12.2%, respectively, in the form of total daidzein (free plus conjugated daidzein). Conclusion: Absorption of daidzein solution was better than absorption of suspension ( P

In patients with chronic end-stage liver disease, the peak plasma concentrations of ropivacaine after a single intravenous ropivacaine dose are similar to those in healthy subjects. However, patients with end-stage liver disease have about a 60% lower mean ropivacaine clearance than healthy subjects and are thus expected to have over two-fold higher steady-state ropivacaine plasma concentrations during a continuous ropivacaine infusion. The peak plasma concentrations of ropivacaine after an axillary plexus block in uraemic patients are considerably higher than those in non-uraemic patients. However, uraemic patients have significantly higher alpha-1-acid glycoprotein plasma concentrations than non-uraemic patients, and the peak plasma concentrations of free ropivacaine (related to toxicity) are similar in both groups. The pharmacokinetics of intravenously administered ropivacaine in patients with renal insufficiency and the possibility of clinically significant (S)-2',6'-pipecoloxylidide metabolite accumulation during continuous or repeated ropivacaine administration in these patients remain to be clarified.

The purpose of this study was to investigate the effect of verapamil on the pharmacokinetic parameters of paclitaxel (50 mg/kg) when paclitaxel is co-administered with verapamil (1, 5, and 15 mg/kg) or pretreated with verapamil (5 mg/kg) for 0.5 h, 3 days, and 6 days orally in rats. When paclitaxel was either co-administered or pretreated with verapamil, the peak plasma concentrations (C(max)) of paclitaxel with verapamil were significantly higher (p0.05 at 5 mg/kg and 0.5 h; p0.01 at 15 mg/kg, 3 days and 6 days) than that of the control. The areas under the plasma concentration-time curve (AUC) of paclitaxel with verapamil were significantly (p0.05 at 5 mg/kg and 0.5 h; p0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control. The AUCs of paclitaxel were increased with verapamil in the dose dependent manner. The half-life (t(1/2)) of paclitaxel with verapamil was significantly prolonged compared with that of the control, except for 1 mg/kg co-administration. The absolute bioavailability of paclitaxel with verapamil (3.9-5.4%) was significantly (p0.05 at 5 mg/kg and 0.5 h; p0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control (2.2%). The relative bioavailability of paclitaxel pretreated with verapamil was higher than that of co-administration in rats. Based on these results, it might be considered that the pharmacokinetic parameters of paclitaxel was significantly affected by verapamil which is an inhibitor of the metabolizing enzyme (CYP3A4) in the intestinal mucosa and liver, and the p-glycoprotein efflux pump in the intestinal mucosa. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with verapamil.

The plasma concentration profiles of four randomly chosen ivermectin (IVM) generic formulations (IVM G1-G4) were compared after their subcutaneous (SC) administration to healthy calves. The disposition of other avermectin-type endectocide compounds, doramectin (DRM) and abamectin (ABM), was also assessed in the same pharmacokinetic trial. Forty-two parasite-free Aberdeen Angus male calves were randomly allocated into six treatment groups. Animals in each group (n = 7) received SC treatment (200 microg/kg) with one of the commercially available endectocide formulation used in the trial. Blood samples were taken into heparinised vacutainer tubes from the jugular vein prior to and up to 35 days post-treatment. The recovered plasma was analysed by HPLC with fluorescence detection. Large kinetic differences were observed among the DRM, ABM and IVM formulations under evaluation. The DRM plasma concentration profiles were higher than those measured for ABM and all the IVM generic formulations. The higher and sustained plasma concentrations of DRM accounted for greater area under concentration-time curve (AUC) and longer mean residence time (MRT) values compared to those obtained for both ABM and the IVM generic preparations. The pattern of IVM absorption from the site of subcutaneous administration showed differences among the generic formulations under evaluation. The IVM G2 preparation showed higher peak plasma concentration and AUC values (P < 0.05) compared to those obtained after the administration of the IVM G1 formulation. Longer (P < 0.05) MRT values were obtained after the administration of the IVM G3 compared to other IVM generic preparations. The kinetic behaviour of ABM did not show significant differences with that described for most of the IVM formulations. This study demonstrates that major differences on drug kinetic behaviour may be observed when using different endectocide injectable formulations in cattle.

Malaria caused by Plasmodium falciparum is responsible for approximately 80% of the incidence and 90% of deaths which occur in the World Health Organization (WHO) African region, with children and pregnant women having the highest incidence. P. falciparum has developed resistance, and therefore new effective candidate antimalarial drugs need to be developed. Previous studies identified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates; therefore, derivatives of these compounds were synthesized in order to improve their desired properties and pharmacokinetic (PK) properties of the derivatives were investigated in a mouse model which was dosed orally and intravenously. Collected blood samples were analyzed using liquid chromatography coupled to mass spectrometer (LC-MS/MS). The mean peak plasma level of 1.9 μM was obtained at 1 hour for compound 1 and 3.3 μM at 0.5 hours for compound 2. A decline in concentration was observed with a half-life of 2.53 and 0.87 hours for compound 1 in mice dosed orally and intravenously, respectively. For compound 2 a half-life of 2.96 and 0.68 hours was recorded. The bioavailability was 69% and 59.7% for compound 1 and compound 2, respectively.

The aim of this study was to compare the profile of circulating concentrations of LH, progesterone and oestradiol in a multiple ovulating male line with that of a single ovulating line of traditional turkeys. Plasma samples from seven traditional and 12 male-line turkeys were obtained every 3 h for 36 h. Male-line and traditional turkeys had single peaks of LH and progesterone that were of similar duration in both lines. The mean height of the plasma peaks of LH and progesterone were similar in the two lines and there was no detectable peak plasma oestrogen concentration. Mean plasma concentrations of LH and oestrogen were higher in single compared with multiple ovulating turkeys, whereas there were no differences in mean plasma progesterone concentrations. The results indicate that the multiple ovulation state in genetically selected high-growth lines of turkey may be the result of a correlated response in the steroidogenic capacity of ovarian tissue associated with low plasma concentrations of oestrogen rather than of a disturbance in the hormone profile of the ovulatory cycle.

Life-threatening complications may occur in body-packers and the rupture of a single packet containing cocaine may lead to fatality. We report the case of a 35-year-old body-packer who developed at the airport clinical signs of cocaine toxicity. There was evidence of bowel obstruction. The plasma concentration of cocaine, benzoylecgonine (BZE) and ecgonine methyl ester (EME) was determined 1 h after symptoms onset, during surgery and postoperative period. The measured peak value at 1 h was 594 ng/ml for cocaine, 9423 ng/ml for BZE and 3261 ng/ml for EME. We confirm the following order BZE > EME > cocaine for peak plasma concentrations. A rebound in plasma levels was found during surgery, together with electrocardiographic changes. A total of 107 packets were eliminated, and the patient survived.