Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats

Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of quercetin on the absorption and disposition of cyclosporin in pigs and rats. Cyclosporin (Sandimmune, 10 mg/kg) was orally administered with and without a concomitant dose of quercetin (50 mg/kg) to pigs and rats. Cyclosporin concentrations in blood samples were determined by a specific monoclonal fluorescence polarization immunoassay. The pharmacokinetic parameters were calculated by noncompartmental analysis using WINNONLIN. A paired Student's t-test was conducted for statistical comparison. A study using the everted intestinal sac was carried out to evaluate the effect of quercetin on the function of intestinal Pgp. The coadministration of quercetin significantly decreased cyclosporin AUC(0-3) (area under the concentration-time curve from time zero to 3 h) by 56% and AUC(0-t) (area under the concentration-time curve from time zero to the last point) by 43% in pigs and rats, respectively, indicating that the coadministration of quercetin significantly decreased cyclosporin oral bioavailability. However, the inverted sac study showed that quercetin significantly inhibited the function of intestinal Pgp. It is suggested that concurrent use of quercetin or quercetin-containing dietary supplement or herbs with cyclosporin or other medications whose absorption and metabolism are mediated by Pgp and/or CYP3A4 should require close monitoring.     

On Assessment of Bioequivalence for Drugs with Negligible Plasma Levels

In bioavailability studies, bioequivalence between drug products is usually determined based on some pharmacokinetic responses such as area under the blood or plasma concentration-time curve and maximum concentration. For some drug products, however, we may have negligible plasma levels because their intended routes of administration. In this case, assessment of bioequivalence between drug products of this kind may be established using clinical endpoints such as therapeutic response and time to the onset of a therapeutic response. In this paper, we propose two procedures which modify the method of generalized estimating equations (Liang and Zeger, 1986) and the proportional hazard models for paired failure times to assess bioequivalence between two drug products under the structure of a standard two-sequence, two-period crossover design. An example concerning a bioequivalence trial for albuterol metered dose inhaler indicated for acute bronchospasm (Herson, 1991) is used to illustrate the proposed procedures.     

Fiber-based liquid-phase micro-extraction of mebeverine enantiomers followed by chiral high-performance liquid chromatography analysis and its application to pharmacokinetics study in rat plasma

The applicability of two-phase liquid-phase micro-extraction (LPME) in porous hollow polypropylene fiber for the sample preparation and the stereoselective pharmacokinetics of mebeverine (MEB) enantiomers (an antispasmodic drug) in rat after intramuscular administration were studied. Plasma was assayed for MEB enantiomer concentrations using stereospecific high-performance liquid chromatography with ultraviolet detection after a simple, inexpensive, and efficient preconcentration and clean-up hollow fiber-based LPME. Under optimized micro-extraction conditions, MEB enantiomers were extracted with 25 μl of 1-octanol within a lumen of a hollow fiber from 0.5 ml of plasma previously diluted with 4.5 ml alkalized water (pH 10). The chromatographic analysis was carried out through chiral liquid chromatography using a DELTA S column and hexane-isopropyl alcohol (85:15 v/v) containing 0.2% triethylamine as mobile phase. The mean recoveries of (+)-MEB and (-)-MEB were 75.5% and 71.0%, respectively. The limit of detection (LOD) was 3.0 ng/ml with linear response over the concentration range of 10-2500 ng/ml with correlation coefficient higher than 0.993 for both enantiomers. The pharmacokinetic studies showed that the mean plasma levels of (+)-MEB were higher than those of (-)-MEB at almost all time points. Also, (+)-MEB exhibited greater t(max) (peak time in concentration-time profile), C(max) (peak concentration in concentration-time profile), t(1/2) (elimination half-life), and AUC(0-240 min) (area under the curve for concentration versus time) and smaller CL (clearance) and V(d) (apparent distribution volume) than its antipode. The obtained results implied that the absorption, distribution, and elimination of (-)-MEB were more rapid than those of (+)-MEB and there were stereoselective differences in pharmacokinetics.     

Influence of ruminal bypass on the pharmacokinetics and efficacy of benzimidazole anthelmintics in sheep

Oxfendazole, fenbendazole and albendazole were each administered at 5mgkg(-1) to sheep fitted with abomasal cannulae as a single bolus intra-ruminally or infused intra-abomasally at a declining exponential rate, with half-life equivalent to the rate of rumen fluid outflow. The pharmacokinetic disposition of parent compound and metabolites in plasma and abomasal fluid was determined by high performance liquid chromatography. Compared with intra-ruminal administration, intra-abomasal infusion of fenbendazole lowered the area under the concentration-time curve of drug in both plasma and abomasal fluid; intra-abomasal infusion of albendazole substantially increased maximum drug concentration and the concentration-time curve in abomasal fluid and lowered the plasma concentration time curve of the sulphoxide metabolite; intra-abomasal infusion of oxfendazole increased maximum concentration and the concentration-time curve of drug in plasma and abomasal fluid. The greater availability in abomasal fluid of oxfendazole and albendazole when given at commercial dose rates of 5 mg kg(-1) and 3.9 mg kg(-1), respectively, by intra-abomasal infusion correlated with increased efficacy of both drugs against benzimidazole-resistant Trichostrongylus colubriformis and of albendazole against benzimidazole-resistant Haemonchus contortus over that achieved by intra-ruminal administration as a single bolus.     

The oral bioavailability and toxicokinetics of methylmercury in common loon (Gavia immer) chicks

We compared the toxicokinetics of methylmercury in captive common loon chicks during two time intervals to assess the impact of feather growth on the kinetics of mercury. We also determined the oral bioavailability of methylmercury during these trials to test for age-related changes. The blood concentration-time curves for individuals dosed during feather development (initiated 35 days post hatch) were best described by a one-compartment toxicokinetic model with an elimination half-life of 3 days. The data for birds dosed following completion of feather growth (84 days post hatch) were best fitted by a two-compartment elimination model that includes an initial rapid distribution phase with a half-life of 0.9 days, followed by a slow elimination phase with a half-life of 116 days. We determined the oral bioavailability of methylmercury during the first dosing interval by comparing the ratios of the area under the blood concentration-time curves (AUC(0--> infinity )) for orally and intravenously dosed chicks. The oral bioavailability of methylmercury during the first dosing period was 0.83. We also determined bioavailability during both dosing periods using a second measure because of irregularities with intravenous results in the second period. This second bioavailability measure estimated the percentage of the dose that was deposited in the blood volume (f), and the results show that there was no difference in bioavailability among dosing periods. The results of this study highlight the importance of feather growth on the toxicokinetics of methylmercury.     

Computer-assisted method for multi-exponential curve fitting for determining cerebral blood flow.

A computer program has been developed for use in determining cerebral blood flow using an inert radioactive gas. The basic algorithm involves the determination of multiple exponential coefficients from the complex concentration-time function. The exponential coefficients are determined by 'peeling' away slower exponentials complex function one at a time. The procedure involves the use of a small laboratory computer in the interactive graphics mode. The method is currently in use analyzing data in a cerebral vascular research laboratory.     

Assessment of rate constants for isolating a metabolite by a model-independent method]

A model-independent method for estimating an elimination rate constant of a metabolite of exogenous substance is suggested as an alternative to known methods. The new method (named the initial slope method) uses blood (plasma) concentration-time data of both the substance and the metabolite obtained after an extravascular impulse input of the substance. The metabolite input is not needed substantially facilitating the experiment. The method is based upon the assessment of areas under the substance and metabolite concentration-time curves, the initial substance concentration, and the initial slope of the metabolite concentration-time curve. The method was tested using artificial data generated on the basis of a compartment model for the substance and metabolite kinetics. It was shown providing nonbiased estimates of a true metabolite elimination rate constant irrespective of the structure of the model used to generate data. Other methods failed to provide such estimates.     

Effects of inflammatory disease on plasma oxprenolol concentrations.

When single oral doses of oxprenolol were given to three healthy subjects on three separate occasions under standardised conditions the plasma concentration-time curves for each subject were closely similar. In two of the subjects, however, a mild illness led to a dramatic, temporary increase in the peak plasma concentration and area under the plasma concentration-time curve (AUC). This effect of inflammatory disease was confirmed by comparing a group of patients with an erythrocyte sedimentation rate (ESR) of over 20 mm in the first hour with a group whose ESR was below this value. The mean peak plasma concentration and AUC were significantly higher in the group with a raised ESR. This may be related to altered concentrations of one of the acute-phase proteins. Thus it is concluded that plasma oxprenolol concentrations are raised in inflammatory disease, but further work is needed to determine the mechanism of this increase.     

肝移植患者他克莫司谷血药浓度监测意义和临床个体化用药调节

目的:探讨移植术后监测他克莫司血药浓度意义和临床药物剂量个体化调节方法。方法:70例肝移植患者术后采用口服他克莫司,每天两次的用药方案,分别在移植后1周和3周监测血液中他克莫司浓度以及外周血单核细胞中钙调磷酸酶活性。结果:移植3周比1周时他克莫司的清除率显著提高。每个采样时间的药物浓度都与0-12 h的浓时间曲线(AUC0-12)下方的面积呈显著的正相关。钙调磷酸酶最低活性与0-12 h的钙调磷酸酶活性-时间曲线显著相关(r20.92)。结论:谷浓度监测是对成年生物配体原位肝移植患者常规他克莫司用药剂量调整的最佳方法,同时监测患者钙调磷酸酶最低活性有助于估计患者在他克莫司用药间隔期的免疫状况。     

Pharmacokinetic interaction with digoxin and glucocorticoids in rats detected by radio-immunoassay using a novel specific antiserum

We previously prepared a more specific antiserum (Antiserum-I) to digoxin (Dx) compared with commercially available anti-Dx antiserum (Antiserum-II), clinically used in the therapeutic drug monitoring of Dx. The aims of this study are to compare Dx disposition kinetics by radio-immunoassay (RIA) using Antiserum-I and Antiserum-II, and evaluate the drug-drug interaction with Dx and glucocorticoids in rats. When Dx metabolites were added to rat serum containing Dx, the recovery ratios using Antiserum-I showed 100 to 110% and were remarkably lower than those using Antiserum-II. In rats, serum concentration-time courses of Dx after a single i.v. or p.o. administration of Dx (0.017 mg/kg) by RIA using Antiserum-I were much lower than those using Antiserum-II. The area under the concentration-time course of Dx was significantly lower than that using Antiserum-II and the total body clearance values were significantly higher, while an obvious change of bioavailability was not observed. When using Antiserum-I, rats twice and six times pretreated with dexamethasone (75 mg/kg/day, i.p.) and prednisolone (69 mg/kg/day, i.p.), respectively, showed significant change of the pharmacokinetic parameters of Dx compared with the control rats. In contrast, using Antiserum-II, it took three and nine times of pretreatment with dexamethasone and prednisolone, respectively, to significantly change the parameters of Dx. In conclusion, these results demonstrate that Antiserum-I is very useful not only to more precisely monitor serum Dx levels, but also to determine earlier the drug-drug interaction with glucocorticoids than Antiserum-II.     

Effect of subacute DDT on pharmacokinetics of isoniazid and liver function in rabbits

DDT administration (30 mg/kg per day, po, for 21 consecutive days) to rabbits showed an increase in peak plasma concentration and a decrease in time to reach peak plasma concentration of isoniazid whereas no change was observed in elimination rate constant and area under the plasma concentration-time curve. DDT treatment caused increased absorption of isoniazid. Early signs of hepatic damage were also observed. Since there was no change in the levels of serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase, it can be concluded that DDT does not significantly affect liver function at the dosage used. The observed elevated levels of alkaline phosphatase could be due to direct activation of the enzyme. Leukopaenia and neutropaenia with relative lymphocytosis indicated that DDT might have suppressant effect on granulocyte cell line of WBCs.     

Pharmacokinetics and liver uptake of three Schisandra lignans in rats after oral administration of liposome encapsulating β-cyclodextrin inclusion compound of Schisandra extract

Schisandra chinensis fructus (SCF) is widely used traditional Chinese medicine, which possesses hepato-protective potential. Schisandrin (SD), schisantherin (ST), and γ-schizandrin (SZ) are the major bioactive lignans. The main problem associated with the major bioactive lignans oral administration is low oral bioavailability due to the lignans’ poor aqueous solubility and taste. The aim of the present research work was to develop liposome (SCL) encapsulated β-cyclodextrin (β-CD) inclusion complex loaded with SCF extract (SCF-E). The SD, ST, and SZ were selected as effective candidates to perform comparisons of liver targeting among the solution (SES), β-cyclodextrin inclusion compound (SCF-E-β-CD), liposome (SEL), and SCL of SCF-E to characterize the pharmacokinetic behaviors and liver targeting in rats. The β-CD inclusion complex (SCF-E-β-CD) was used to improve the solubility. The concentrations were determined using high-performance liquid chromatography (HPLC) and analyzed by DAS3.0. The pharmacokinetic results indicate that the plasma concentration-time courses were fitted well to the one-compartment model with the first weighing factor. The half-life period (t_1/2) and area under the concentration-time curve (AUC) of the three components in SCL were the largest. The SCL exhibit a relatively high liver targeting effect. The results would be helpful for guiding the clinical application of this herbal medicine.     

Estimation of the rate and extent of chiral inversion using linear systems analysis

An alternative method based on linear systems analysis is presented for the analysis of concentration-time data for the enantiomers of the 2-arylpropionic acids. This approach uses deconvolution to estimate the rate and extent of chiral inversion with respect to time, assuming linear pharmacokinetics and time invariance, without the need for complicated modelling procedures. Application to data for the chiral inversion of ibuprofen in the rat indicates that this approach provides a valid alternative to previous procedures for the analysis of chiral inversion data. © 1995 Wiley-Liss, Inc.     

Investigation of the pharmacokinetics of gemcitabine and 2',2'-difluorodeoxyuridine in human plasma by liquid chromatography

Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against solid tumors. The pharmacokinetics of dFdC and its metabolite, 2',2'-difluorodeoxyuridine (dFdU) have been studied; however, their disposition has never been evaluated in a patient with bladder cancer. A patient with bladder cancer was treated with dFdC 1000 mg/m(2) over a 30min period. The patient received a dFdC infusion once per week for 3 weeks followed by a rest week. Serial plasma samples were obtained prior to, during, and after completion of the infusion for determination of dFdC and dFdU concentrations. dFdC and dFdU concentrations were measured using normal-phase high-performance liquid chromatography and one-compartment open model methods. Maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve for dFdC and dFdU were 24.5 microg/ml and 11200 microg/Lh, 49.1 microg/ml and 272,800 microg/Lh, respectively.     

Two doses of humanized anti-CD25 antibody in renal transplantation

AUC, area under the concentration-time curve; CGN, chronic glomerulonephritis; Cl, Clearance rates; Cmax, maximum serum concentration; CsA, cyclosporin A; CV, coefficient of variation; DGF, delayed graft function; ELISA, enzyme-Linked immunosorbent assay; ESRD, end-stage renal disease; FITC, fluorescein isothiocyanate; HRP, horseradish peroxidase; LOQ, limit of quatitation; MMF, mycophenolate mofetil; PD, pharmadynamics; PE, phycoerythrin; PK, pharmacokinetics; QC, quality control; SAE, serious adverse event; T1/2ke, terminal half-life; TBS, bovine serum albumin in tris buffered saline; Tmax, time to reach the peak concentration; TBST, Tris-Buffered Saline Tween-20; Vd, volumes of distribution     

Pharmacokinetics of Peptide mediated delivery of anticancer drug ellipticine

The amino acid pairing peptide EAK16-II (EAK) has shown the ability to stabilize the hydrophobic anticancer agent ellipticine (EPT) in aqueous solution. In this study, we investigate pharmacokinetics of the formulation of EAK-EPT complexes in vivo. The developed formulation can achieve a sufficiently high drug concentration required in vivo animal models. The nanostructure and surface properties of EAK-EPT complexes or nanoparticle were characterized by transmission electron microscopy (TEM) and zeta potential measurements, respectively. 12 healthy male SD rats were divided into EPT group and EAK-EPT group randomly. Rats in EPT group were tail intravenously injected with the EPT (20 mg/kg); rats in EAK-EPT group were injected with EAK-EPT complexes (EPT's concentration is 20 mg/kg). EPT was extracted from rat plasma with dexamethasone sodium phosphate as internal standards (IS). The pharmacokinetic parameters were obtained using high pressure liquid chromatography (HPLC). Significant differences in main pharmacokinetic parameters between EPT and EAK-EPT complexes were observed, demonstrating that the complexation with EAK prolongs the residence time of the drug and enlarges the area under the concentration-time curve (AUC). This means that EAK can serve as a suitable carrier to increase the bioavailability of EPT.     

Pharmacokinetic data of propranolol enantiomers in a comparative human study with (S)- and (R,S)-propranolol

The pharmacokinetics of (S)-propranolol were compared after the oral administration of a 40 mg dose of the pure enantiomer and an 80 mg dose of a racemic mixture of (R,S)-propranolol. The results of this study indicate that the bioavailability of (S)-propranolol, as expressed by the mean area under the concentration-time curve (AUC) and maximum serum concentration, is lower after 40 mg of the optically pure drug than after the racemic drug.     

In vitro and in vivo evaluation of oridonin-loaded long circulating nanostructured lipid carriers

The purpose of this study was to develop poly(ethylene glycol)-coated nanostructured lipid carriers (PEG-NLC) for parenteral delivery of oridonin (ORI) to prolong drug circulation time in blood. Oridonin-loaded PEG-NLC (ORI-PEG-NLC) consisting of PEG(2000)-stearate, glycerol monostearate and medium chain triglycerides were prepared by emulsion-evaporation and low temperature-solidification technique. Oridonin-loaded NLC (ORI-NLC) were also prepared as control. ORI-PEG-NLC were observed by transmission election microscope and the morphology was in rotiform shape. The mean particle size of ORI-PEG-NLC was 329.2 nm and entrapment efficacy was 71.18%. The results of differential scanning calorimetry and X-ray diffraction revealed a low-crystalline structure of ORI and verified the incorporation of ORI into the nanoparticles. In vitro drug release of ORI-PEG-NLC exhibited biphasic drug release patterns with burst release initially and prolonged release afterwards. Pharmacokinetic analysis showed that the mean residence time of ORI-PEG-NLC was prolonged and AUC (area under tissue concentration-time curve) value was also improved compared with ORI-NLC and ORI solution. In conclusion, ORI-PEG-NLC could be a potential carrier to get prolonged retention time of oridonin in blood.     

Investigation of the pharmacokinetics and determination of tramadol in rabbit plasma by a high-performance liquid chromatography-diode array detector method using liquid-liquid extraction

An HPLC system using a new, simple and rapid liquid-liquid extraction and high-performance liquid chromatography-diode array detector method (HPLC-DAD) detection was validated to determine tramadol concentration in rabbit plasma. The method described was applied to a pharmacokinetic study of intravenous tramadol injections in rabbits. The extraction with ethylacetate yielded good response. The recovery of tramadol from plasma averaged 90.40%. Serial plasma samples were obtained prior to, during and after completion of the infusion for determination of tramadol concentrations. Tramadol concentrations were measured using reverse-phase high-performance liquid chromatography and pharmacokinetic application with intravenous tramadol in rabbits revealed that tramadol followed one-compartment open model. Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) for tramadol were 14.3 microg mL(-1) and 42.2 microg h mL(-1), respectively. The method developed was successfully applied to a simple, rapid, specific, sensitive and accurate HPLC method for investigation of the pharmacokinetics of tramadol in rabbit plasma.