Animals ; Biopharmaceutics ; Blood-Brain Barrier ; Chromatography ; methods ; Intestinal Absorption ; Membranes, Artificial ; Pharmacokinetics ; Skin Absorption ; Tissue Distribution

In this study, the biopharmaceutical properties of 20 (S)-protopanaxadiol (PPD) were studied. Firstly, the equilibrium solubility and apparent oil/water partition coefficient of PPD were used to predict the absorption in vivo. Meanwhile the membrane permeability and absorption window were studied by Caco-2 cell model and single-pass intestinal perfusion model. Furthermore, the bioavailability and metabolism were combined to study the absorption properties and metabolic properties in vivo. All of them were used to provide theoretical and practical foundation for designing PPD preparation. The results showed that PPD is poorly water-soluble, and the equilibrium solubility in water is only 35.24 mg x L(-1). The oil-water partition coefficient is 46.21 (logP = 1.66). By Caco-2 cell model, the results showed PPD uptake in general, and it also has efflux. By in situ intestinal perfusion model, the results showed that the absorption of PPD in the intestine is good, and the effective permeability coefficient were duodenum > jejunum > ileum > colon. The oral bioavailability of PPD was 29.39%. It was not well. Metabolic studies showed PPD in vivo presented a wide spread metabolism. So the main factors that restricted oral bioavailability of PPD were the poor solubility and first-pass effect.
Administration, Oral ; Animals ; Area Under Curve ; Biological Availability ; Caco-2 Cells ; Humans ; Intestinal Absorption ; Male ; Permeability ; Rats ; Rats, Sprague-Dawley ; Sapogenins ; administration & dosage ; blood ; chemistry ; metabolism ; pharmacokinetics ; Solubility ; Tissue Distribution

OBJECTIVETo study the pharmacokinetics and bioequivalence of asparaginase loaded in hyaluronic acid-graft-poly(ethylene glycol)/ sulfobutylether-β-cyclodextrin nanocapsules (AHSP) in SD rats.

METHODSThe morphology of AHSP was observed under the transmission electron microscope and the particle size and zeta potential were measured. AHSP and free asparaginase were intravenously injected in rats, and the plasma asparaginase activity was measured at different time points after the injections. The pharmacokinetic parameters were calculated using the software DAS 2.1.1 to assess the bioequivalence of AHSP and free asparaginase.

RESULTSAHSP had an average particle size of 413.80∓10.97 nm with a zeta potential of -20.37∓2.38 mV. The AUC(0-48 h) of AHSP and free asparaginase was 137.34∓1.82 U/mL and 46.38 ∓1.98 U/mL, and their AUC(0-∞) was 164.66∓6.88 U/mL and 51.44∓3.01 U/mL with half-lives of 4.62∓0.60 h and 1.86∓0.38 h, respectively. Compared with free AN, AHSP exhibited increased AUC(0-48 h), AUC(0-∞), and half-life by 2.24, 2.55 and 2.32 folds, respectively. The 90% confidential intervals of AUC(0-48 h), AUC(0-∞) and Cmax of the tested formulation were 75.0%-76.5%, 74.3%-76.1%, and 95.1%-96.7%, respectively.

CONCLUSIONAHSP can improve the bioavailability and extend the biological half-life of asparaginase in rats, and AHSP and free asparaginase are not bioequivalent.

Animals ; Area Under Curve ; Asparaginase ; pharmacokinetics ; Biological Availability ; Half-Life ; Injections, Intravenous ; Nanocapsules ; Rats ; Rats, Sprague-Dawley ; Therapeutic Equivalency

OBJECTIVETo evaluate the bioequivalence of orally disintegrating tablets of pentoxyverine citrate (tested preparation) in healthy male volunteers.

METHODSA single oral dose of the tested and reference preparations at 25 mg were given to 20 healthy volunteers in a randomized two-period cross-over design. Plasma pentoxyverine citrate concentrations were determined by HPLC-MS/ESI+ method. The pharmacokinetic parameters were calculated and the bioequivalence of the two preparations were evaluated using DAS program.

RESULTSThe Tmax, Cmax, AUC0 15 and AUC0infinity of tested and reference preparations were 1.62-/+0.75 h and 2.52-/+1.21 h, 62.28-/+33.06 microg/L and 59.72-/+33.25 microg/L, 234.44-/+130.01 microg.h.L(-1) and 228.77-/+129.24 microg.h.L(-1), 246.80-/+136.19 microg.h.L(-1) and 244.11-/+140.73 microg.h.L(-1), respectively. The 90% confidence interval of C(max), AUC0 15 and AUC0infinity of tested preparations were 81.4%-138.4%, 86.0%-123.3% and 86.5%-121.2%, respectively.

CONCLUSIONThe tested and reference preparations are bioequivalent.

Adult ; Area Under Curve ; Biological Availability ; Citric Acid ; administration & dosage ; pharmacokinetics ; Cross-Over Studies ; Cyclopentanes ; administration & dosage ; pharmacokinetics ; Humans ; Male ; Tablets ; Therapeutic Equivalency ; Young Adult

Acteoside (verbascoside), a phenylethanoid glycoside widely distributed in various plants, has been shown to have potential activity against Alzheimer's disease, attracting great attentions recently. The present study was designed to develop a selective and sensitive LC-MS/MS method for the determination of acteoside in biological samples and carry our a pharmacokinetic (PK) study in beagle dogs. The PK parameters were calculated using non-compartmental models. Following a single-dose oral administration, acteoside was rapidly absorbed and eliminated, with Tmax being between 30 to 45 min and terminal half-life being about 90 min. The areas under the time-concentration curve (AUC) were 47.28 ± 8.74, 87.86 ± 13.33, and 183.14 ± 28.69 mg · min · L(-1) for oral administration of 10, 20, and 40 mg · kg(-1), respectively, demonstrating that the exposure of acteoside proportionally increased with the dose level. The absolute bioavailability of acteoside was around 4%. For all the PK parameters, there were large variations between individual dogs. In conclusion, the pharmacokinetic characteristics observed in the present study can be of great value to help better understand the pharmacological properties of acteoside and to improve the outcome of its clinical use.
Administration, Intravenous ; Administration, Oral ; Alzheimer Disease ; drug therapy ; Animals ; Area Under Curve ; Biological Availability ; Chromatography, High Pressure Liquid ; Dogs ; Female ; Glucosides ; pharmacokinetics ; Intestinal Absorption ; Male ; Phenols ; pharmacokinetics ; Plant Extracts ; pharmacokinetics ; Tandem Mass Spectrometry ; Verbenaceae ; chemistry

Metformin, an oral antihyperglycemic agent, is widely used as the first-line pharmacotherapy for type 2 diabetes mellitus (T2DM). It has been in use for several decades as numerous different formulations. However, despite its use, population pharmacokinetic (PK) modeling of metformin is not well developed. The aim of the present study was to evaluate the effect of formulation on PK parameters by developing a population PK model of metformin in Koreans and using this model to assess bioequivalence. We used a comparative PK study of a single agent and a fixed-dose combination of metformin in 36 healthy volunteers. The population PK model of metformin was developed using NONMEM (version 7.3). Visual predictive checks and bootstrap methods were performed to determine the adequacy of the model. The plasma concentration-time profile was best described by a two-compartment, first-order elimination model with first-order absorption followed by zeroorder absorption with lag time. From the covariate analysis, formulation had significant effect (p < 0.01) on relative bioavailability (F = 0.94) and first-order absorption constant (Ka = 0.83), but the difference was within the range of bioequivalence criteria. No other covariate was shown to have significant effect on PK parameters. The PK profile of the disposition phase was consistent with the published literature. However, in the present study, the multiple peaks found during the absorption phase implied the possible diversity of absorption PK profile depending on formulation or population. Unlike traditional bioequivalence analysis, the population PK model reflects formulation differences on specific parameters and reflected simulation can be performed.
Absorption ; Adult ; Biological Availability ; Diabetes Mellitus, Type 2 ; Drug Therapy ; Healthy Volunteers ; Humans ; Metformin ; Pharmacokinetics ; Plasma ; Therapeutic Equivalency

OBJECTIVETo prepare diazepam transdermal gel and to assess its bioavailability.

METHODSUsing Carbopol 934 as a gel matrix, the diazepam transdermal gel was prepared with glycerol as the humectant and azone as penetration enhancer. The penetration rate of diazepam through excised rabbit skin was measured by Franz diffusion cell and HPLC method. Using diazepam tablets as control, the relative bioavailability of diazepam gel was determined in rabbits.

RESULTSThe transdermal flux of diazepam gel was 39.26 g/cm(2)/h and the bioavailability of diazepam gel was 36.25%.

CONCLUSIONDiazepam gel prepared in the study would be developed as a novel transdermal preparation.

Administration, Cutaneous ; Animals ; Biological Availability ; Diazepam ; administration & dosage ; pharmacokinetics ; Drug Compounding ; Gels ; pharmacokinetics ; Rabbits ; Skin Absorption

AIMTo develop an HPLC-MS assay for determination of donepezil in human plasma and to investigate the pharmacokinetics and bioequivalence of donepezil capsule in healthy volunteers.

METHODSA randomized crossover design was performed in 20 healthy volunteers. In the two study periods, a single 5 mg dose of either capsule or tablet was administered to each volunteer. After spiked with the internal standard (phenoprolamine) and treated with saturated sodium bicarbonate, plasma was extracted with ethyl acetate and separated with a C18 reversed phase column. LC-ESIMS was used in the selected ion monitoring (SIM) mode with target ions at m/z 380 for donepezil and m/z 344 for phenoprolamine. The fragmentor voltage was 120 V. The main pharmacokinetic parameters of donepezil and the bioequivalence of its two preparations were calculated.

RESULTSThe main pharmacokinetic parameters T1/2, Tmax and Cmax were (63 +/- 10) h, (3.3 +/- 0.4) h and (8.5 +/- 0.4) microgram.L-1 for the capsule; (57 +/- 9) h, (3.4 +/- 1.0) h and (8.1 +/- 1.0) microgram.L-1 for the tablet, respectively. The relative bioavailability of the donepezil capsule was 102% +/- 11%.

CONCLUSIONThe assay was shown to be sensitive, accurate and convenient. The two preparations of donepezil were bioequivalent.

Adult ; Area Under Curve ; Biological Availability ; Capsules ; chemistry ; Cholinesterase Inhibitors ; administration & dosage ; pharmacokinetics ; Chromatography, High Pressure Liquid ; Cross-Over Studies ; Humans ; Indans ; administration & dosage ; pharmacokinetics ; Male ; Piperidines ; administration & dosage ; pharmacokinetics ; Spectrometry, Mass, Electrospray Ionization ; Tablets ; chemistry ; Therapeutic Equivalency

OBJECTIVETo study the pharmacokinetics and bioavailability of ginkgolides sustained-release tablet and conventional tablet in Beagle dogs.

METHODThe concentrations of ginkgolides in plasma were determined by LC-MS. The main pharmacokinetic parameters of ginkgolides sustained-release tablet and conventional tablet in vivo were obtained using Pharmacokinetic software DAS 2.0.

RESULTThe C(max) of grinkgolide A in ginkgolide sustained-release tablet and conventional tablet were 443.51, 1 039.30 microg x L(-1), respecitvely. t(max) were 2.92, 1.08 h, respectively. AUC(0-12h) were 1 808.21, 2 041.37 h x microg(-1) x L(-1), respectively. MRT were 5.18, 3.18 h, respectively. The relative bioavailability of ginkgolides A was 88.58%. The C(max) of ginkgolide B in ginkgolide sustained-release tablet and conventional tablet were 407.13, 547.38 microg x L(-1), respectively. t(max) were 2.92, 1.08 h, respectively. AUC(01-12 h) were 1 987.31, 1 748.04 h x microg(-1) x L(-1), respectively. MRT were 6.05, 4.98 h, respectively. The relative bioavailability of ginkgolides B was 113.69%.

CONCLUSIONThe ginkgolides sustained-release tablets have good sustained release characteristics and are bioequivalent to the reference formulation.

Animals ; Area Under Curve ; Biological Availability ; Chromatography, High Pressure Liquid ; methods ; Delayed-Action Preparations ; administration & dosage ; pharmacokinetics ; Dogs ; Ginkgolides ; administration & dosage ; analysis ; pharmacokinetics ; Lactones ; analysis ; Male ; Mass Spectrometry ; methods ; Quality Control ; Tablets ; administration & dosage ; pharmacokinetics ; Therapeutic Equivalency

The Qinbai Qingfei concentrated pellets by traditional Chinese medicine theoryand party and group, the rats were given the drugs group, comparison of pharmacokinetics parameters changes of baicalin , discusses the rationality of Qinbai prescription. The rats were gavaged monarch drug group (Huang Qincu extract, mainly forbaicalin), and official medicine group, adjuvant group, medicine group and Qinbai group (Quan Fangzu) the content of baicalin equal as the monarch drug group, in the 28 h collection in rat plasma at different time point, application of HPLC determination of baicalin glycosides in rat plasmaconcentration time curve, with 3P97 practical pharmacokinetics program to process the data Based on the data analysis, baicalin in rat plasma of Qinbai group Cmax is 4 times as big as monarch druggroup, AUC is 6 times as big as monarch drug group; the content of baicalin in plasma of rats the highest is Qinbai group, the minister drug group, adjuvant group, medicine group of baicalin in rat plasma content of less than the Qinbai group, but was significantly higher than that of monarch drug group; the medicine group is slightly higher than that adjuvant the content of baicalin in plasma of rats. The pharmacokinetic results show that the measured plasma concentration in rats that Qinbai can significantly increase Cmax and AUC of baicalin, other components of qinbai can promoted the baicalin absorption in vivo. It showed that the reasonable of Qinbai compound compatibility. The minister drug can promote the absorption of baicalin in vivo.
Animals ; Area Under Curve ; Drugs, Chinese Herbal ; analysis ; pharmacokinetics ; Flavonoids ; blood ; pharmacokinetics ; Intestinal Absorption ; Male ; Rats ; Rats, Wistar