Weibull function C = Bts-1exp(-lambda ts) was used to describe plasma concentration-time data of ribavirin in 6 healthy subjects following an i.v. dose of 600 mg. A good fit was found in each of the subjects, where the coefficients of determination r2 were > 0.99. The parameters estimated were as follows: B, 5.90 +/- 1.86 micrograms.h1-s; lambda, 0.607 +/- 0.156 h-s; and s, 0.339 +/- 0.085, respectively. The results were compared with those by triexponential function. By providing lower values of AIC and SD, as well as higher values of r2, the Weibull function proved to be superior to triexponential function for data of 3 subjects. These results indicated that both Weibull function and triexponential function provided a good fit of plasma concentration-time data of ribavirin in man following an i.v. dose.

Adult↗

PubMedDate not supplied

Cefixime absorption kinetics after oral administration to humans.

Cefixime (CFX) absorption kinetics after oral administration to humans was studied. Four distinct models, incorporating a delay of absorption and first-order elimination kinetics, i.e. first-order absorption (M1), zero-order absorption (M0), Michaelis-Menten type absorption (MM) and Michaelis-Menten type absorption with 'an absorption window' (MM-delta t) were used to fit concentration data of CFX in 10 Chinese men following an oral dose of 400 mg. r2 and AIC were selected as measures of goodness-of-fit. The results show that the MM-delta t model provided a better fit than the other three models. The kinetic parameters were estimated as follows: Vmax' = 10.80 +/- 3.80 mg.l-1.h-1; K(m)' = 88.31 +/- 2.75 micrograms.ml-1; delta t = 4.75 +/- 0.85 h; T1/2 = 4.20 +/- 0.92 h; Tmax = 5.20 +/- 0.92 h; and Cmax = 6.04 +/- 1.70 mg.l-1.

Absorption↗

PubMedDate not supplied

Trapezoidal area method for simulating physiological pharmacokinetics of drugs in animals.

A trapezoidal area method for simulating physiological pharmacokinetics of drugs in animals is proposed. Concentrations of ethoxybenzamide in rat tissues and diazepam in human plasma were simulated. The results showed that profiles of concentrations vs time in the body with this method were in a good agreement with those obtained with the Rang-Katta method. As compared with the Rang-Katta method, the present method has two special advantages: the time course of drug concentration in tissue can be estimated using simple equations and the speed for simulation is faster.

Animals↗

PubMedDate not supplied

A double-site absorption model fits to pharmacokinetic data of repaglinide in man.

The plasma concentrations of repaglinide in 16 male subjects were determined after an oral dose of 4 mg. Two-peak concentrations in plasma were observed. A type of one-compartment model with double sites of drug absorption was developed and successfully used to fit the data. A good agreement between observed and predicted data was found in all subjects with correlation index r2 > 0.97. The corresponding pharmacokinetic parameters were estimated as follows: Tmax1 0.61 +/- 0.14 h, Tmax2 1.45 +/- 0.43 h, Cmax1 40.60 +/- 20.57 ng/ml, Cmax2 42.70 +/- 17.54 ng/ml, T1 0.12 +/- 0.07 h, T2 0.67 +/- 0.30 h and T3 1.03 +/- 0.35 h.

Absorption↗

PubMedDate not supplied

Gender difference in ranolazine pharmacokinetics in rats.

Pharmacokinetics of ranolazine (RAN) in both female and male rats was studied. RAN concentrations in plasma were determined after oral administration of 12.5, 25 and 50 mg/kg RAN. Concentrations in tissues, recoveries of RAN in urine and bile were also analyzed following oral dose of 25 mg/kg. It was found that plasma concentrations of RAN in female rats were significantly higher than those in male rats. Drug exposures based on Cmax and AUC in female rats were roughly 2-to 3-fold of those in male rats. Terminate half-life T1/2 and MRT in male rats were shorter than those in female rats. The recoveries in urine and bile of female rats were also markedly higher than those in male rats'. Tissue concentrations of RAN in female rats were also markedly higher than those in male rats. These results demonstrated existence of marked gender difference in RAN pharmacokinetics in rats.

Acetanilides↗

PubMedDate not supplied

Gender differences in limonin pharmacokinetics in rats.

In the present study, the pharmacokinetics of limonin (LM) were investigated in male and female rats. LM concentrations in the plasma were determined after the oral administration of 36 mg/kg LM or after intravenous (i.v.) injection of LM 3.6 mg/kg respectively. Concentrations in the tissues, urine, feces and bile were also analyzed following the oral administration of 36 mg/kg of the test product. It was found that the plasma concentrations of LM in female rats were significantly higher (P < 0.01) than those in male rats. Assessment of the effects of limonin based on the C(max) and AUC in female rats showed that levels were about 50-fold higher than those in male rats after oral administration of 36 mg/kg LM. Furthermore, after i.v. administration of 3.6 mg/kg LM, the C(max) and AUC in female rats was found to be about 3-fold higher than those in male rats. The total excretion of LM in the urine and bile of female rats was also found to be significantly higher than in male rats, which displayed lower concentrations of LM in the tissues, amounting to around one-half to one-tenth of those in female rats, apart from levels in the rectum and duodenum. In conclusion, the present results demonstrate the existence of marked gender difference in LM pharmacokinetics in rats.

Administration, Oral↗

PubMedDate not supplied

Correlation between quinolone uptakes by BCECs in vitro and brain-to-plasma concentration ratios in rats.

Transport of 11 quinolones at the blood-brain barrier (BBB) was studied in vitro by using primarily cultured rat brain capillary endothelial cells (BCECs) and in vivo brain-to-plasma concentration ratios. In vitro, when cells reached confluence, a time course of quinolone uptake was recorded by incubation with a medium contraining quinolones 20 microg/ml at 37 degrees C. A simple two-compartment model was used for fitting the uptake time course and corresponding uptake parameters were estimated. In vivo rats were anesthetized, after in 10 mg/kg of quinoloes followed by infusion of 4 mg/kg/h for 2 hours, the drug concentrations in plasma and brain were measure and brain-to-plasma concentration ratios were calculated. Result showed that sparfloxacin and prulifloxacin have higher uptakes by BCECs and brain-to-plasma concentration ratios, compared with other quinolones, which indicated that the two drugs more easily penetrate into BBB. A good correlation between uptakes by BCECs and brain-to-plasma concentration ratios was found. These results demonstrated uptakes by BCECs in vitro might give prediction of brain-to-plasma ratio for quinolones.

Animals↗

PubMedDate not supplied

Effect of P-glycoprotein inhibitors erythromycin and cyclosporin A on brain pharmacokinetics of nimodipine in rats.

Effect of P-glycoprotein (P-gp) inhibitors erythromycin (Ery) and cyclosporin A(CsA) on brain pharmacokinetics of nimodipine (NMD) in rats was studied. NMD concentrations in rat plasma and brain were determined after iv 2 mg/kg NMD alone, co-administration with Ery and CsA, respectively. It was found that concentrations of NMD in plasma of the three groups had a little difference, but brain concentrations of NMD in rats co-administrated with Ery and CsA were significantly higher than those in rats NMD alone. Significances of NMD in rat brain were found at 20, 40, 60 and 90 min after iv NMD. The brain T(1/2) in rat treated with ery(75.0 min) and CsA(79.0 min) were larger than that (44.2 min) in rats NMD alone. The results indicated that P-gp inhibitors Ery and CsA may increase concentration in rat brain by inhibiting elimination of NMD from brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Prediction of drug clearance in humans from laboratory animals based on body surface area.

The object of the study was to develop a new allometric equation for clearance from laboratory animals to humans based on body surface area (BSA allometric method). Human clearances for 30 drugs were predicted from animal data obtained from the literature. The results predicted with the method were compared with those observed. The results were also compared with values predicted with clearance versus body weight (BW simple allometric method), the product of brain weight and clearance versus body weight (Cl x BRW method) and the product of maximum life span potential and clearance versus body weight (Cl x MLP method), respectively. Good predictions were found in 21 out of 30 with the BAS allometric method. Both BSA allometric method and BW simple allometric method can give good predictions of clearance in humans for many drugs. Similarly to BW simple allometric method, Cl x BRW method and Cl x MLP method, BSA allometric method may be used to accurately predict human clearance from laboratory animal data.

Animals↗

PubMedDate not supplied

Different effect of erythromycin on absorption kinetics of nimodipine in male and female rats.

Effect of erythromycin (ERY) on oral absorption of nimodipine (NMD) in female and male rat was investigated in vivo and in vitro. In vivo, at 15 min following oral dose of 50 mg/kg ERY, an oral dose 20 mg/kg NMD was given to rats, plasma concentrations of NMD were determined. In vitro, everted jejunum sac and ileum sac were used, NMD transport from mucosal side to serol side was measured, in absences of ERY and cyclosprin A (CSA) or in presence of ERY and CSA. Large gender difference was found after oral dose NDM. Male rats had lower plasma concentration than female rat did. AUC180 and Cmax in male rats were less than 5-folds and 3-folds than those in female rats, respectively. Co-administrating ERY may increase plasma concentrations of NMD in rats. AUC180 in male rats and female rats were 2.2-folds and 1.9-folds of those NMD alone, respectively. Cmax was about 3-folds of that NMD alone. The NMD transport in intestine showed a regional variation and gender differences. In female rat, transport rate in the jejunum was about 1.3 higher than ileum. Both ERY and CSA significant increases transport of NMD. Contrast to female, NMD transport in jejunum was lower that that in ileum. Bothe ERY and CSA had little effect on NMD transport in intestine. These results indicated that there existed gender difference in oral absorption of NMD and effect of ERY on oral absorption kinetics of NMD in female rats was different from that in male rat.

Animals↗

PubMedDate not supplied

Glucocorticoids augment fibroblast-mediated contraction of collagen gels by inhibition of endogenous PGE production.

Glucocorticoids are currently regarded as the drug of choice in the treatment of inflammatory airway and lung diseases, however, they are not routinely effective in fibrotic phases of inflammation. In the current study, glucocorticoids were investigated for their ability to affect fibroblast mediated contraction of a three dimensional collagen gel, a measure of one aspect of tissue remodeling. Dexamethasone, budesonide, hydrocortisone and fluticasone propionate were all able to significantly augment fibroblast contractility in a concentration dependent manner. Glucocorticoids also had an augmentative effect on collagen gel contraction mediated by fibroblasts from bronchi, skin and bone marrow. The increased contractility was not due to cell proliferation or to collagen degradation, since the glucocorticoids did not alter the amounts of DNA and hydroxyproline in the gels. The concentration of prostaglandin E2 (PGE2) in supernatant media was lower from glucocorticoid-treated gels compared to control gels. Consistent with this, addition of exogenous PGE2 to the culture system restored the contractile properties and indomethacin augmented contraction similar to the glucocorticoids suggesting that inhibition of prostaglandins or related eicosanoids may be the mechanism by which the increased contractility occurs. DBcAMP, forskolin and the long lasting beta2-agonist formoterol were able to reverse the effect of the glucocorticoids on fibroblast mediated collagen gel contraction suggesting that enhancers of cAMP can counteract the effect of glucocorticoids. Thus, we provide evidence that glucocorticoids have the ability to directly augment fibroblast contractility by inhibiting fibroblast endogenous PGE synthesis. The findings could be one possible mechanism to explain the poor therapeutic response to glucocorticoids on the later stages of fibrotic diseases.

Animals↗

PubMedDate not supplied

Characterization of structure and diffusion behaviour of Ca-alginate beads prepared with external or internal calcium sources.

Ca-alginate beads were prepared with either external or internal calcium sources. The structures of both beads were investigated with the aid of scanning electron microscopy (SEM) and confocal microscopy. It was shown that the beads with internal calcium source had a looser structure and bigger pore size than those with external calcium source. The attempts to interpret the difference were carried out by determining the Ca content within the beads at various times, which indicated that it was the different gelation mechanisms that caused the difference of structures of both beads. Furthermore, it was also found that the diffusion rate of haemoglobin (Hb) within the beads with an internal calcium source was faster than that of the beads with an external one, which was consistent with the observation of their structures.

Alginates↗

PubMedDate not supplied

Geographic pathology on the precursors of stomach cancer.

The classification of dysplasias of the gastric mucosa used in our institute includes adenomatous dysplasia, regenerative dysplasia, and cryptal dysplasia. We compared the incidence of gastric dysplasia in three regions of China which have quite different geographical environments: the loess plateau of Wuwei area in the Gansu Province, the island of the Yangtze River in the Jiangsu Province of southern China, and the coastal area of the Liaoning Province in northern China. The mortality rate of stomach cancer in these areas is more than 50 per 100,000. We found a total of 323 cases of gastric dysplasia in these three areas. Regenerative dysplasia is the most common precancerous lesion of the stomach and was found in 40% of the cases from the three high-risk areas of gastric cancer. The background lesions consist of gastric erosions, severe gastritis, gastric ulcers, and intestinal metaplasia, which indicate that some factors causing damage to gastric mucosa are very important in the histogenesis of stomach cancer. The gastric dysplasia sites involved are different in the three geographical regions studied. On the island of the Yangtze River, cardiac dysplasia and intestinal metaplasia are common (75%), and cancer of the cardia is also common. In the other two geographical areas, antral dysplasia predominates (85 to 91%). The finding of different sites of gastric dysplasia in different geographical environments may be very important in our search for etiological factors of gastric cancer and may allow for beneficial intervention in the prevention of this disease.

Adult↗