Elimination Half-time Research Articles

Evaluation of Tetrandrine Sustained Release Calcium Alginate Gel Beads <i>In Vitro</i> and <i>In Vivo</i>

An approach for the preparation of tetrandrine sustained release calcium alginate gel beads was described. In vitro the release of tetrandrine from sustained release dosage forms went on a time of 12 hours which fitted non-Fickian diffusion with matrix erosion significantly. In vivo the plasma concentration of tetrandrine extended preparation given in dogs reached Cmax 2.67+/-0.69 microg/ml approximately at 5.67+/-0.58 h after oral administration. The AUC0-->24 and AUC0-->infinity were 24.64+/-6.77 mg.h/l and 29.75+/-5.30 mg.h/l, respectively. The elimination half-time was 9.6+/-2.40 h. While a favorable correlation existed between in vitro and in vivo with a correlative coefficient of 0.9798 through linear regression. An investigation on the quantitative relationship between in vitro release and in vivo absorption is a highly necessary work guided for manufacture, optimization and in vivo evaluation of sustained release dosage by means of in vitro release or dissolution tests.

Exploratory population pharmacokinetics (e-PPK) analysis for predicting human PK using exploratory ADME data during early drug discovery research

We have proposed a novel method by population pharmacokinetics analysis for forecasting the drug concentration time-course in humans. This method is based on the non-linear mixed effect model (NONMEM) combined with in vitro-in vivo extrapolation (IVIVE). Eleven clinically tested compounds were selected for retrospective analysis. The in vivo pharmacokinetic (pk) profiles (rats, dogs, monkeys, and humans) and in vitro ADME data [intrinsic clearance (CLint), plasma unbound fraction (fp), and blood-plasma partition ratio (Rb)] for each compound was routinely tested via a screening system to account for inter-compound differences in pk properties. When evaluating the pk parameters, the hepatic plasma flow (Qph) and plasma volume (Vp) were taken into account to compensate for differences in body size among species. All these data were used to conduct population pk (PPK) analyses under the hypothesis that all species constituted one population. The two-compartment model (ADVAN4 TRANS3) and NONMEM software were used for this analysis. The fixed effect model for total body clearance (CL) and central distribution volume (Vd) were constructed as theta(CL)Qph x Eh and theta(Vd) x Vp, respectively, where the hepatic extraction ratio Eh was calculated using the traditional dispersion model. NONMEM generates both fixed and random effects (eta). The key point of this concept was to substitute the eta values of each species (rats, dogs, and monkeys) into the human PPK model to simulate three kinds of pk profiles, compound by compound, for use as a general scaling factor. The NONMEM post hoc option was used to perform the simulation, after which the concentration vs. time courses were compared with actual clinical pk data. The true values were almost within the dynamic range. Thus, the advantage of this concept is that it can generate time-courses without the detail of drug-specific parameters, from which the elimination half time can be determined. This proposed exploratory population pharmacokinetic (e-PPK) approach is a useful and progressive tool that can be applied during the early stages of drug discovery research.

Morphine uptake, disposition, and analgesic efficacy in the common goldfish (Carassius auratus)

The purposes of the present study were to examine the rate of morphine uptake in goldfish ( Carassius auratus (L., 1758)) when administered via the water, to calculate the pharmacokinetics of morphine when administered intraperitoneally, and to determine whether morphine could act as an analgesic. When administered via the water, morphine uptake was very slow, and the concentration accumulated in the plasma was <1% of that in water after 2 h. Furthermore, changing water pH or hardness caused small changes in morphine uptake from the water, but plasma levels remained <1% of water concentrations after 2 h exposure. The pharmacokinetics of morphine administered intraperitoneally (40 mg/kg) revealed a half-time for elimination of 37 h and a mean residence time of 56 h. Finally, morphine acted as an analgesic when administered via the water as demonstrated by significantly decreased rubbing behaviour in response to the presence of a noxious stimulus (subcutaneous injection of 0.7% acetic acid). Although morphine appeared to have analgesic properties in goldfish, morphine administered via ambient water is not recommended because of its slow rate of uptake.

Pharmacokinetics of acetaminophen administered in tablets and capsules under long-term space flight conditions

The pharmacokinetics of acetaminophen in two medicinal forms, tablets and capsules, have been studied in healthy volunteers after single peroral administration at a dose of 500 mg under usual living conditions and during long-term space flight. The rate of drug absorption from tablets decreases significantly whereas the relative bioavailability increases substantially under microgravity conditions (compared with usual conditions). For the encapsulated medicinal form, the time of absorption decreases statistically reliably and the half-elimination time, the average retention time, and the distribution volume increase considerably whereas the bioavailability changes insignificantly.

Plasma pharmacokinetics and tissue distribution of [6]‐gingerol in rats

[6]-Gingerol is one of the pungent components in ginger which has been found to possess various pharmacological effects. However, there is insufficient information on the properties of [6]-gingerol based on controlled pharmacokinetic studies. The aim of this study was to clarify distribution profiles of [6]-gingerol in blood and biological tissues of experimental rats. Rats were administered a 240 mg/kg dose of Gs (a ginger extract, containing 53% [6]-gingerol) by oral ingestion. Plasma samples were collected at 2.5, 5, 7.5, 10, 15, 20, 30, 45 min, and 1, 1.5, 2, 3, 4 h after dosing (eight samples per time point), and brain, heart, lung, spleen, liver, kidney, stomach and small intestine tissues were collected at 5, 15, 30 min and 1, 2, 4 h after dosing (five animals per time point). Samples were prepared by a liquid-liquid extraction procedure and the extracts were assayed by HPLC-UV. After per oral application, [6]-gingerol was absorbed rapidly into the plasma, and the maximal concentration (4.23 microg/ml) was reached after 10 min post dosing. [6]-Gingerol plasma concentrations declined with time in a biexponential pattern. The elimination half-time at the terminal phase was 1.77 h and the apparent total body clearance was 40.8 l/h. When administered orally, [6]-gingerol was well distributed to the tissues examined, with the highest concentrations found in the gastrointestinal tract. Maximal concentrations of [6]-gingerol were reached in most tissues at 0.5 h post-dosing. The concentrations of [6]-gingerol in tissues all were higher than in plasma with corresponding tissue to plasma ratios greater than 1 after 0.25 h post-dose, showing high tissue partitioning and extensive distribution.

Intraocular Pharmacokinetics of Bevacizumab After a Single Intravitreal Injection in Humans

To investigate intraocular concentrations and pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Prospective, noncomparative, interventional case series. We included 30 nonvitrectomized eyes of 30 patients (age range, 43 to 93 years) diagnosed with clinically significant cataract and concurrent macular edema secondary to neovascular age-related macular degeneration, diabetic retinopathy, or retinal venous occlusion in the same eye. All patients received an intravitreal injection of 1.5 mg bevacizumab. Between one and 53 days after injection, an aqueous humor sample was obtained during elective cataract surgery. Concentrations of unbound bevacizumab in these samples were quantified by enzyme-linked immunosorbent assay. Concentration of bevacizumab in aqueous humor peaked on the first day after injection with a mean concentration (c(max)) of 33.3 microg/ml (range, 16.6 to 42.5 microg/ml) and subsequently declined in a monoexponential fashion. Nonlinear regression analysis determined an elimination half-time (t(1/2)) of 9.82 days (R(2) = 0.81). No significant differences between diagnosis subgroups were noted. In human nonvitrectomized eyes, the aqueous half-life of 1.5 mg intravitreally injected bevacizumab is 9.82 days.

Pharmacokinetics and metabolism of Dihydroquercetin isolated from Larix sibirica Ledeb

The aim of this study was the investigation of the pharmacokinetic processes of Dihydroquercetin isolated from Larix sibirica Ledeb (DHQ; CAS N° 480–18–2, C15H12O7; 2,3-dihydro-2-(3,4-dihydroxyphenil)-3,5,7-trihydroxyphenil-4H-1-benzopyran-4-on; 3,5,7,3',4'-penta-hydroxyflavon) and identification it metabolites in blood plasma and urine after single intravenous, oral administration (12.5, 50mg/kg) in rats. Blood plasma and urine samples of rats, containing DHQ-glucuronide were underwent enzymatic hydrolysis with purified β-glucuronidase solution (1). Hydrolyzed samples were extracted with diethyl ether from acidic medium. Quantification of DHQ was performed by reverse-phase HPLC with UV- and MS-detection. It was established that DHQ is a short-living drug (the half-elimination time was not exceed of 1.25h). The drug was determined for 6h in rats. Absolute bioavailability is about 24%. 8.30% of DHQ from administered oral dose (250mg/kg) was excreted with daily urine. Analyzed compound was not detected in feces. In daily urine were detected and preliminary identified in addition to unchanged substance 7 products its biotransformation: stereoisomer of DHQ, methylated metabolite of DHQ, stereoisomer of methylated metabolite of DHQ, DHQ-glucuronide, stereoisomer of DHQ-glucuronide, methylated metabolite of DHQ-glucuronide and stereoisomer of methylated metabolite of DHQ-glucuronide.

Toxicokinetics Of 2,3,7,8-TCDF and 2,3,4,7,8-PeCDF in Mink (Mustela vison) at Ecologically Relevant Exposures

Wild mink (Mustela vison) living along the Tittabawassee River in central Michigan exhibit elevated hepatic and dietary polychlorinated dibenzofuran (PCDF) concentrations exceeding mink-specific, literature-reported toxicity reference values (TRVs) on a toxicity equivalents basis. However, no apparent effects on individuals or population are evident, suggesting that available TRVs may overpredict risk for the site-specific mix of congeners. To investigate this discrepancy, a 180-day spiked feed study was conducted to assess: (1) the dosages of key congeners necessary to achieve liver concentrations bracketing those observed in wild mink, (2) time to achieve steady-state concentrations, and (3) effect of coadministration of 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) on the toxicokinetics and distribution of each congener. Adipose and hepatic PCDF concentrations were measured at 0, 90, and 180 days. PCDF concentrations in mink scat were determined at several time points and indicated nearly complete absorption of both TCDF and 4-PeCDF from the diet. Elimination half-times of TCDF were < 15 h and were inversely proportional to dose, while those for 4-PeCDF were approximately 7-9 days with no clear dose dependency in the tested dose range. Coadministration of 4-PeCDF and TCDF accelerated clearance of TCDF compared to administration of TCDF alone. Clearance of 4-PeCDF was not affected by TCDF coadministration. Distribution of 4-PeCDF, but not TCDF, demonstrated increased hepatic sequestration with increasing dose. 4-PeCDF toxicokinetics were described using a previously published two-compartment model. Overall, the toxicokinetic information gathered here illustrates the impact of CYP1A1 induction on bioaccumulation and toxicity potential of TCDF and 4-PeCDF. This information may provide insight into why the current TRVs do not appear to correctly characterize the risk for these two congeners when they are the primary components of an environmental mixture.

Pharmacokinetics of levofloxacin after single and multiple oral doses in patients undergoing intermittent haemodialysis

The impact of intermittent haemodialysis (IHD) on the pharmacokinetics of levofloxacin after single and multiple oral doses of 500 mg was assessed in 10 patients with end-stage renal failure on IHD. In the first phase of the study where a single dose was administered, IHD was initiated 90 min after drug intake. In the second phase of the study where drug was administered daily for three consecutive days, IHD was started exactly after the first dose. Venous blood samples were collected at standard time intervals. Additional samples from the arterial and venous line of the fistula and from the dialysate were drawn at the first, second and fourth hour of the first IHD session. Levofloxacin concentrations were estimated by high performance liquid chromatography analysis using fluorescence detection. Median (±standard error) pharmacokinetic parameters after single and multiple dosing, respectively, were: maximum plasma concentration ( C max) 5.04 ± 0.87 mg/L and 8.32 ± 0.64 mg/L; area under the concentration–time curve with extrapolation to infinity (AUC 0→Inf) 190.24 ± 29.23 mg h/L and 720.79 ± 75.57 mg h/L; elimination half-time ( t 1/2) 22.84 ± 5.56 h and 38.05 ± 4.14 h; and clearance rate 2.67 ± 0.39 L/h and 2.10 ± 0.21 L/h. Removal of levofloxacin by IHD was indicated by a significant decrease in concentration from the arterial line to the venous line of the fistula. The C max/MIC and AUC 0→24/MIC ratios (where MIC is the minimum inhibitory concentration of the pathogen) remained above >100 and >10, respectively, rendering levofloxacin a candidate for infections in these patients.

Pharmacokinetics of the potent redox-modulating manganese porphyrin, MnTE-2-PyP 5+, in plasma and major organs of B6C3F1 mice

Mn(III) tetrakis( N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP 5+, a potent catalytic superoxide and peroxynitrite scavenger, has been beneficial in several oxidative stress-related diseases thus far examined. Pharmacokinetic studies are essential for the better assessment of the therapeutic potential of MnTE-2-PyP 5+ and similar compounds, as well as for the modulation of their bioavailability and toxicity. Despite high hydrophilicity, this drug entered mitochondria after a single 10 mg/kg intraperitoneal injection at levels high enough (5.1 μM; 2.95 ng/mg protein) to protect against superoxide/peroxynitrite damage. Utilizing the same analytical approach, which involves the reduction of MnTE-2-PyP 5+ followed by the exchange of Mn 2+ with Zn 2+ and HPLC/fluorescence detection of ZnTE-2-PyP 4+, we measured levels of MnTE-2-PyP 5+ in mouse plasma, liver, kidney, lung, heart, spleen, and brain over a period of 7 days after a single intraperitoneal injection of 10 mg/kg. Two B6C3F1 female mice per time point were used. The pharmacokinetic profile in plasma and organs was complex; thus a noncompartmental approach was utilized to calculate the area under the curve, c max, t max, and drug elimination half-time ( t 1/2). In terms of levels of MnTE-2-PyP 5+ found, the organs can be classified into three distinct groups: (1) high levels (kidney, liver, and spleen), (2) moderate levels (lung and heart), and (3) low levels (brain). The maximal levels in plasma, kidney, spleen, lung, and heart are reached within 45 min, whereas in the case of liver a prolonged absorption phase was observed, with the maximal concentration reached at 8 h. Moreover, accumulation of the drug in brain continued beyond the time of the experiment (7 days) and is likely to be driven by the presence of negatively charged phospholipids. For tissues other than brain, a slow elimination phase (single exponential decay, t 1/2 = 60 to 135 h) was observed. The calculated pharmacokinetic parameters will be used to design optimal dosing regimens in future preclinical studies utilizing this and similar compounds.

Pharmacokinetics and bioavailability of the new drug protecor upon peroral administration in rabbits and beagle dogs

A new high-performance liquid chromatographic method with ultraviolet detection has been used to determine the levels of the new cardiotropic drug protecor in the blood of animals (chincilla rabbits, 2.2 ± 0.2 kg; and beagle dogs, 10 ± 0.5 kg). The parameters of protecor pharmacokinetics and bioavailability upon peroral administration of protecor tablets have been determined. Rabbits showed effective absorption of the drug uupon peroral administration in a single dose (100 mg/kg) with a peak concentration in the plasma (Cmax= 41 µg/mL) reached within Tmax= 3 h followed by rapid removal of the drug from the organism with a half-elimination time T/12β=1.71 h. Peroral administration of protecor in a single dose (50 mg/kg) in beagle dogs was characterized by Cmax= 34.6 µg/mL, Tmax = 3 h, and T/12β=0.75 h. The bioavailability of protecor upon peroral administration was estimated at 90% (rabbits) and 80.7% (beagle dogs).

Polarographic study of sydnophen excretion from rat organism

The urinary excretion of sydnophen from rat organism has been studied using a polarographic technique for the first time. It is shown that approximately one third of the introduced drug dose is excreted unchanged with urine within 24 h. The elimination rate constant (Kel = 0.11 h−1) and half-elimination time (t1/2 = 6.3 h) are indicative of a low rate of sydnophen removal from rat organism. The proposed polarographic technique has proven to be reliable and convenient and is recommended for studying the clinical pharmacokinetics of sydnophen.

Modelling the lactate response to short-term all out exercise

BackgroundThe maximum post exercise blood lactate concentration (BLCmax) has been positively correlated with maximal short-term exercise (MSE) performance. However, the moment when BLCmax occurs (TBLCmax) is rather unpredictable and interpretation of BLC response to MSE is therefore difficult.MethodsWe compared a 3- and a 4-parameter model for the analysis of the dynamics of BLC response to MSEs lasting 10 (MSE10) and 30 s (MSE30) in eleven males (24.6 ± 2.3 yrs; 182.4 ± 6.8 cm; 75.1 ± 9.4 kg). The 3-parameter model uses BLC at MSE-start, extra-vascular increase (A) and rate constants of BLC appearance (k1) and disappearance (k2). The 4-parameter model includes BLC at MSE termination and amplitudes and rate constants of increase (A1, y1) and decrease (A2, y2) of post MSE-BLC.ResultsBoth models consistently explained 93.69 % or more of the variance of individual BLC responses. Reduction of the number of parameters decreased (p < 0.05) the goodness of the fit in every MSE10 and in 3 MSE30. A (9.1 ± 2.1 vs. 15.3 ± 2.1 mmol l-1) and A1 (7.1 ± 1.6 vs. 10.9 ± 2.0 mmol l-1) were lower (p < 0.05) in MSE10 than in MSE30. k1 (0.610 ± 0.119 vs. 0.505 ± 0.107 min-1), k2 (4.21 10-2 ± 1.06 10-2 vs. 2.45 10-2 ± 1.04 10-2 min-1), and A2 (-563.8 ± 370.8 vs. -1412.6 ± 868.8 mmol l-1), and y1 (0.579 ± 0.137 vs. 0.489 ± 0.076 min-1) were higher (p < 0.05) in MSE10 than in MSE30. No corresponding difference in y2 (0.41 10-2 ± 0.82 10-2 vs. 0.15 10-2 ± 0.42 10-2 min-1) was found.ConclusionThe 3-parameter model estimates of lactate appearance and disappearance were sensitive to differences in test duration and support an interrelation between BLC level and halftime of lactate elimination previously found. The 4-parameter model results support the 3-parameter model findings about lactate appearance; however, parameter estimates for lactate disappearance were unrealistic in the 4-parameter model. The 3-parameter model provides useful information about the dynamics of the lactate response to MSE.

Metabolism and pharmacokinetics of the combination Zidovudine plus Lamivudine in the adult Erythrocebus patas monkey determined by liquid chromatography-tandem mass spectrometric analysis

Because of their similarity to humans, non-human primates constitute useful preclinical models in which to examine potential human drug toxicities. Antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) toxicity is currently under investigation in Erythrocebus patas monkeys, and whereas NRTI pharmacokinetics have been studied in other monkey species, pharmacokinetics for Zidovudine plus Lamivudine (AZT/3TC) dosing have not been reported in the patas. Here we present 24 h serum pharmacokinetic parameters after a single oral exposure to the combination of AZT (40 mg) and 3TC (24 mg), doses equivalent to a human daily dose of Combivir®. The patas ( n = 3) AZT/3TC pharmacokinetic profiles were similar to those seen in other primate species. Average maximum serum concentrations ( C max) for AZT and 3TC were 2.35 and 2.65 μg/ml, respectively, and were observed at 0.83 h ( T max). C max was 13.34 μg/ml for the AZT-glucuronide (AZT-G) and was 0.023 μg/ml for the potentially toxic minor metabolite 3′-amino-3′-deoxythymidine (AMT), both occurring at about 1 h after dosing. Similar elimination half-times, 0.70 and 0.68 h − 1 , were found for AZT and AZT-G, respectively, while 3TC was eliminated about half as fast (0.33 h − 1 ) resulting in AUC (0–∞) values of 6.97 μg/ml h for 3TC, 2.99 μg/ml h for AZT, 20.5 μg/ml h for AZT-G and 0.002 for AMT 6.97 μg/ml h. This study shows similar metabolism and pharmacokinetics for oral administration of AZT/3TC in the adult patas monkey, other primate species and humans. The data validate the use of the patas monkey for studies of NRTI toxicity.

HYPOTENSIVE DRUGS EFFECT AND LIVER MONOOXIGENASE FUNCTION IN ARTERIAL HYPERTENSION PATIENTS AFTER ADRENAL HYPERFUNCTION CORRECTION

Hypotensive drug tolerance and liver monooxygenase activity were investigated in 24 refractory arterial hypertension patients before and after surgical suppression of adrenal hyperfunction. Liver monooxygenase activity was studied using antipyrine test. It was found that hypotensive drug tolerance was decreased after one and two side operations on adrenal glands. In parallels halftime of antipyrine elimination was shown to be prolonged by 88.5% in 3 months - 3 years after suppression of adrenal hyperfunction. Our findings suggest that the hypotensive drug tolerance diminution may be the consequence of liver monooxygenase activity reduction. This assumption is in accordance with well known the hypotensive drug metabolism by microsomal liver monooxygenases

Endothelial cell dysfunction after coronary artery bypass grafting with extracorporeal circulation in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus is a well-known risk factor in patients with severe coronary artery disease undergoing coronary artery bypass grafting (CABG). The aim of the study was to analyze the endothelial dysfunction in these patients by evaluating postoperative soluble inflammatory cytokines. Patients undergoing CABG without (n=15, group A) and with (n=14, group B) diabetes mellitus were analyzed for their release of E-selectin, interleukin-6 (IL-6), and tumor necrosis factor (TNF) up to 3 days postoperatively. A pharmacokinetic quantitative kinetic evaluation (Kinetica 2000) of maximum concentrations (c(max)), time to reach c(max) (t(max)), area under the curve (AUC(0-inf)), and terminal elimination half time (t(1/2)) was performed using a non-compartmental model. There was no difference in preoperative plasma concentrations of the cytokines and in the postoperative kinetic analyses of TNF when comparing both groups. However, the release of IL-6 was restricted with c(max) of 1055+/-543 pg/ml for group B versus 2112+/-1532 pg/ml for group A (p< or =0.05), paralleled by a decrease in the absolute amount (AUC(0-inf)) of IL-6. The t(1/2) remained unaffected (13.9+/-6.6h and 12.7+/-4.6h, respectively). The AUC(0-inf) of E-selectin decreased by a factor of 1.7 (p< or =0.05) with unchanged c(max) but reduced t(1/2) (12.9+/-10h for group B vs 33.1+/-20.4h for group A; p< or =0.01) referring to an augmented endothelial uptake and degradation of E-selectin. CABG with extracorporeal circulation could be used to verify a specific endothelial dysfunction in diabetic patients characterized by an impaired release of IL-6 and an increased turnover of E-selectin.

Live Cell Imaging of Outward and Inward Vesiculation Induced by the Complement C5b-9 Complex

Cells resist death induced by the complement membrane attack complex (MAC, C5b-9) by removal of the MAC from their surface by an outward and/or inward vesiculation. To gain an insight into the route of MAC removal, human C9 was tagged with Alexa Fluor 488 and traced within live cells. Tagged C9-AF488 was active in lysis of erythrocytes and K562 cells. Upon treatment of K562 cells with antibody and human serum containing C9-AF488, C9-AF488 containing MAC bound to the cells. Within 5-10 min, the cells started shedding C5b-9-loaded vesicles (0.05-1 mum) by outward vesiculation. Concomitantly, C9-AF488 entered the cells and accumulated in a perinuclear, late recycling compartment, co-localized with endocytosed transferrin-Texas Red. Similar results were obtained with fixed cells in which the MAC was labeled with antibodies directed to a C5b-9 neoepitope. Inhibition of protein kinase C reduced endocytosis of C5b-9. Kinetic analysis demonstrated that peripheral, trypsin-sensitive C5b-9 was cleared from cells at a slower rate relative to fully inserted, trypsin-resistant C5b-9. MAC formation is controlled by CD59, a ubiquitously expressed membrane complement regulator. Analysis at a cell population level showed that the amount of C5b-9-AF488 bound to K562 cells after complement activation was highly heterogeneous and inversely correlated with the CD59 level of expression. Efficient C9-AF488 vesiculation was observed in cells expressing low CD59 levels, suggesting that the protective impact of MAC elimination by vesiculation increases as the level of expression of CD59 decreases.

Avenanthramides Are Bioavailable and Have Antioxidant Activity in Humans after Acute Consumption of an Enriched Mixture from Oats

The consumption of polyphenols is associated with a decreased risk of cardiovascular disease. Avenanthramides (AV), alkaloids occurring only in oats, may have anti-atherosclerotic activity, but there is no information concerning their bioavailability and bioactivity in humans. We characterized the pharmacokinetics and antioxidant action of avenanthramide A, B, and C in healthy older adults in a randomized, placebo-controlled, 3-way crossover trial with 1-wk washout periods. Six free-living subjects (3 mol/L, 3 F; 60.8 ± 3.6 y) consumed 360 mL skim milk alone (placebo) or containing 0.5 or 1 g avenanthramide-enriched mixture (AEM) extracted from oats. Plasma samples were collected over a 10-h period. Concentrations of AV-A, AV-B, and AV-C in the AEM were 154, 109, and 111 μmol/g, respectively. Maximum plasma concentrations of AV (free + conjugated) after consumption of 0.5 and 1 g AEM were 112.9 and 374.6 nmol/L for AV-A, 13.2 and 96.0 nmol/L for AV-B, and 41.4 and 89.0 nmol/L for AV-C, respectively. Times to reach the Cmax for both doses were 2.30, 1.75, and 2.15 h for AV-A, AV-B, and AV-C and half times for elimination were 1.75, 3.75, and 3.00 h, respectively. The elimination kinetics of plasma AV appeared to follow first-order kinetics. The bioavailability of AV-A was 4-fold larger than that of AV-B at the 0.5 g AEM dose. After consumption of 1 g AEM, plasma reduced glutathione was elevated by 21% at 15 min (P ≤ 0.005) and by 14% at 10 h (P ≤ 0.05). Thus, oat AV are bioavailable and increase antioxidant capacity in healthy older adults.

Pharmacokinetics and bioavailability of gentiopicroside from decoctions of Gentianae and Longdan Xiegan Tang after oral administration in rats—Comparison with gentiopicroside alone

The pharmacokinetics and bioavailability of gentiopicroside (GPS), an active component of the Gentian plant species, from orally administered decoctions of Gentianae (DG), or in combination with other plants in the prescription of Longdan Xiegan Tang (LXT), was compared in rats with oral administration of GPS alone, using doses adjusted to deliver equivalent amounts of GPS (150 mg/kg). Changes in plasma levels of GPS following oral administration of GPS or DG could be fitted to a one compartment open model with elimination half times ( T ( 1/2 ) K e ) of 3.35 ± 0.76 h and 6.21 ± 3.07 h, respectively. Kinetics of plasma GPS following oral administration of LXT could be fitted to a two compartments open model with an elimination half time ( T (1/2) β ) of 3.83 ± 1.54 h. The bioavailability of GPS from DG was markedly better, and that from LXT markedly worse, compared with GPS alone, as judged by the area under concentration-time curve (AUC) values of 70.0 ± 13.9 μg h/ml (DG), 32.7 ± 12.9 μg h/ml (GPS) and 19.1 ± 5.9 μg h/ml (LXT). The study demonstrates the marked variability in pharmacokinetics and bioavailability of an active component from different herbal preparations.

Comparison of pharmacokinetics, efficacy and toxicity profile of gemcitabine using two different administration regimens in Chinese patients with non-small-cell lung cancer

To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m(2) gemcitabine using standard 30-min infusion or fixed dose rate (FDR) infusion [10 mg/(m(2) x min)] on days 1 and 8 plus carboplatin AUC (area under curve) 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. The obtained mean parameters, such as T(1/2) (elimination half time), AUC, and CL (clearance), were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR arm. Additional 50% and 33.3% patients contracted stable disease (SD) in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion arm experienced consistently more hematologic toxicity. Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.