The relevance of nitrendipine erythrocyte partitioning for the variability of its bioavailability parameters.

The pharmacokinetic parameters of nitrendipine were determined in 40 healthy male volunteers and a very high degree of intersubject variability was observed (CV = 39-71%). Since the distribution of nitrendipine to erythrocytes could influence the overall pharmacokinetic variability the correlation between hematocrit and various pharmacokinetic parameters was analyzed, using linear regression. In vitro partitioning of nitrendipine to erythrocytes suspended in physiologic saline was studied over a range of hematocrit and drug concentration values. The correlations of in vivo pharmacokinetic parameters were linear with medium to high correlation coefficients (0.65-0.80). The positive correlation between the volume of distribution and hematocrit and negative between AUC, C(max) and beta parameters indicate that nitrendipine enters and/or is bound to erythrocytes. The results of the in vitro erythrocyte partitioning experiments confirm this observations as the mean values of partition coefficient to erythrocytes was found to be 2.85 +/- 0.17.

Effects of ondansetron on portal hemodynamics in liver cirrhosis.

OBJECTIVE: The double-blind randomized pilot study was undertaken to compare the effects of a 10-day course of ondansetron 8 mg/day and propranolol 80 mg/day perorally in treating portal hypertension. SUBIECTS AND METHODS: 16 patients with liver disease were enrolled in the study. Measurements of portal vein diameter, portal blood flow velocity and portal blood flow volume were done at days 1, 5 and 10 of treatment using duplex Doppler sonography. RESULTS: The propranolol group demonstrated a decrease in portal venous diameter, while patients treated with ondansetron exhibited reduced portal blood flow velocity values. A decreased portal blood flow volume was found in both groups after 10 days of therapy. CONCLUSION: No statistically significant differences were found between the groups with the exception of portal venous diameter which is significantly lower at the end of the treatment in the case of propranolol.

Kinetics of 4-fluoroquinolones permeation into saliva.

Following a single oral administration of ciprofloxacin, norfloxacin, pefloxacin and ofloxacin preparations to healthy volunteers simultaneously collected, saliva and plasma 4-fluoroquinolone concentrations were assayed by HPLC. Pharmacokinetic properties were determined by ordinary least squares fitting of the two compartment pharmacokinetic model to the experimental data. A good correlation between plasma and saliva data has been demonstrated. The saliva to venous plasma drug concentration ratio S/P appeared to be time-dependent in the case of norfloxacin and pefloxacin. It was demonstrated that S/P is a function of the quotient of the rate of absorption and venous plasma drug concentration. The calculated S/P ratios with the influence of absorption eliminated, (S/P)(corr) are: ciprofloxacin 0.53+/-0.02, norfloxacin 0.34+/-0.04, ofloxacin 0. 43+/-0.02 and pefloxacin 0.39+/-0.02 (mean+/-S.E.). These values are apparently independent of log D thus making it impossible to predict S/P on the basis of partition principles. The corresponding (S/P)(dif) ratios were calculated on the basis of the assumption that an equilibrium is established across the blood-saliva barrier, which is permeable only for nonionized and nonprotein bound drug fraction. Comparing (S/P)(corr) with the calculated (S/P)(dif) ratios it is evident that 4-fluoroquinolone permeation in saliva cannot be described by passive diffusion based on pH-partition theory.

Eudragit E microspheres containing bacampicillin: preparation by solvent removal methods.

Eudragit E microspheres containing bacampicillin hydrochloride were prepared by solvent evaporation and solvent extraction methods. Three different systems of solvents were used: methyl acetate, acetone and methanol/liquid paraffin. The success of the procedures depended mostly on the lipophilicity of the solvent. The particle size of microspheres was determined by sieve analysis. The results showed that the average size of microspheres is influenced greatly by the type of solvent. Scanning electron microscopy was used for observation of the shape of microspheres. Microspheres prepared by the solvent evaporation method in systems with acetone and methyl acetate were all of a regular spherical shape. The surface of all other microspheres were folded. The influence of magnesium stearate content in microspheres was also studied in terms of different methods, solvents and processing conditions.

Urodynamic modeling of norfloxacin pharmacokinetics by means of computer simulation.

Urodynamic model was developed which, in conjunction with a compartmental pharmacokinetic model, was used for study of factors influencing drug concentrations in urine: urine flow rate, residual bladder urine, maximal bladder urine, stage of renal failure, and elimination kinetics of drugs. Norfloxacin (NOR) was used as a model drug, although the model haw general applicability for all urinary antiseptics. Pharmacokinetic data were obtained from a clinical study in which norfloxacin was administered orally as a single 400mg dose to four subjects with installed urine catheters. Sample of blood, bladder and catheter urine were collected and concentrations of NOR measured by a HPCL method. Modeling was performed on analog--hybrid computer EAI 580. Besides the fitting of model response to obtained in vivo data, simulations of expected clinical situations were performed in which the interplay of above mentioned factors was studied in terms of urine concentrations profiles. NOR treatment with 400mg b.i.d. secured sufficient urine concentrations in most studied cases. This approach should be applied for corresponding study of other urinary antiseptics, especially those with less favourable urinary levels.

Biopharmaceutic evaluation of some 4-quinolone derivatives.

The relationships between physicochemical properties (ionization, solubility, partition, protein binding) of 4-quinolone derivatives and their pharmacokinetics was studied by means of in vitro methods. This information is needed to clarify the erratic absorption behaviour of quinolone antibacterials following oral administration. The ionization constants of ofloxacin (OF), pefloxacin (PF), norfloxacin (NF) and ciprofloxacin (CF) were determined by solubility, potentiometric, spectrophotometric, and octanol-water partition methods. The quinolones are ampholytes showing small values of partition coefficients (order of magnitude 1) resulting from their hydrophilic nature. Within the series, both partition coefficients and the ionization constants differ only slightly (5.5 less than pK1 less than 6.5, and 7.5 less than pK2 less than 8.5). The intrinsic solubility of nonionized forms of drugs was obtained to be of 1g/l order of magnitude. Linear relationship was observed between the log solubility versus reciprocal temperature. The dissolution of NF is an endothermic reaction with dissolution enthalpy H = 20.4 kJ/mol. In vitro diffusion of OF, PF, NF, and CF was studied by the means of Sartorius in vitro absorption model. The rate of diffusion and the projected in vitro rate of absorption are not functions of structural differences within the series (diffusion rate constant range was 0.5 less than kd less than 5.0 .10-3 cm/min). Binding of NF, CF, PF and OF to bovine serum albumin (BSA) was studied using equilibrium dialysis in the absence and presence of urea. It was found that the quinolones were moderately bound (40-60%) to BSA and that urea in pathologic concentrations diminished their binding for 10-25%.

Age-dependent pharmacokinetics of phenylbutazone in calves.

The pharmacokinetics of phenylbutazone (PBZ) in relation to age was studied in calves. The drug was applied intravenously to calves (dose 22 mg/kg), which were divided, depending on age, into three groups. Heparinised blood samples were taken in defined intervals. The concentrations of phenylbutazone and two of its metabolites were determined in plasma by high performance liquid chromatography. The pharmacokinetic data derived from 1-month-old calves revealed a longer persistence (elimination half-lives twice as long, total body clearance 40-50% lower) of PBZ in the body than in the other two groups of calves aged 3-6 months. With respect to the long elimination half-lives (mean values 39-94 h), caution is needed in case of repeated doses (accumulation).

Bioavailability of piroxicam: oral and rectal multiple application in humans.

The aim of the work is to evaluate the bioequivalence of piroxicam administered orally and rectally in 20 mg dose every 24 hours. The corresponding "in vivo" study was undertaken and plasma samples were collected during the ninth dosing interval. HPLC method was used for piroxicam plasma concentrations determination. AUC and C were calculated and the obtained data were statistically analyzed. Analog-hybrid simulation was used to confirm additionally the similarity between the discussed formulations. No significant differences were observed using paired t-test and two-way analysis of variance while the methods of Hauck and Westlake, looking strictly, gave nonbioequivalence. Simulated response of one compartment model is suitable for "in vivo" data in both cases. Measured and simulated average steady state concentrations are equal and in complete accordance with those given in literature. Finally it can be concluded that oral and rectal application are bioequivalent in the sense of expected clinical effects.

The bioavailability of oral nifedipine formulations: a statistical and simulation approach.

The bioequivalence of three oral forms of nifedipine was assessed in a triple crossover study on 12 healthy volunteers. Single 10 mg dose was given and ten blood samples were drawn during the first 8 h after administration. Highly sensitive gas chromatographic method was used for the nifedipine assay. Pharmacokinetic parameters which describe bioavailability and general kinetic behaviour of the drug (AUC, Cmax, tmax, beta, MRT) were calculated from individual plasma profiles. They were subjected to statistical analysis (paired t-test, Hauck's inverted t-test, and Westlake's method of confidence intervals). Analogue-hybrid simulation and identification was used to generate plasma profiles of nifedipine after single and multiple dosing. Averaged plasma concentrations were used for this purpose. The three formulations studied were bioequivalent in terms of the rate of absorption. The simulation proved to be an efficient tool to substitute in vivo multiple dosing studies for assessment of bioavailability. The specific statistical methods should be preferred in bioequivalence data evaluation due to their greater power and inclusion of extraneous bioequivalence limits interval. Despite the differences among the formulations studied, each one of them should be viewed according to its intended clinical use.

Quantitative high-performance thin-layer chromatographic analysis of ampicillin in human urine.

A quantitative high-performance thin-layer chromatographic (HPTLC) method was developed for the analysis of ampicillin in urine. A dioxane-water-n-butanol-formic acid mobile phase system and HPTLC Silica gel 60 F254 as stationary phase were used. Quantitation was realized on a Zeiss PMQ 2 densitometer connected to a Varian A-25 recorder and an Apple II microcomputer or alternatively with an HP 9830A computer and HP 9862A plotter. A good linear range of detection (0.05-1.00 micrograms) at 480 nm was obtained. Standard statistical methods demonstrated good reproducibility (coefficient of variation is not greater than 3%). The method is appropriate for ampicillin quality control and pharmacokinetic studies.

Pharmacokinetics of dihydroergosine in rats after intravenous and oral administration.

Wistar rats received an intravenous dose of 20 micrograms/kg and an oral does of 40 micrograms/kg 3H-Dihydroergosine. Concentrations of radioactivity were measured in plasma, bile, urine, and faeces, and pharmacokinetical parameters of an open two compartment model were calculated. After intravenous injection and oral administration 3H-Dihydroergosine is rapidly lost from the central compartment with distribution rate constants alpha = 0.889 h-1 and beta = 0.722 h-1, respectively. Biological half life in the elimination phase after both application is nearly the same t 1/2 = 13.6 h. The volume of central compartment is Vc = 3.075 l/kg and the volume of distribution Vd beta = 30.75 l/kg. The fraction of 3H-Dihydroergosine absorbed after oral administration, calculated from areas under the curves upon oral and intravenous administration, is 31%. The percentage of 3H-radioactivity eliminated with bile was 98.3% of the dose within 72 hours after intravenous and 29.3% after oral administration. The main portion of the administered 3H-radioactivity was recovered in faeces -66.1% after intravenous and 81.3% after oral administration, while only 17.4% and 4.9% of the administered dose was eliminated in the urine within 120 hours, respectively.

Dihydroergosine pharmacokinetic modelling and simulation.

For this study of dihydroergosine pharmacokinetic modelling and simulation, the data from our paper about 3H-DHESN plasma, bile, urine, and faeces concentrations after intravenous and oral administration were used (1). The model obtained with the identified parameters was in agreement with in vivo data. Certain special phenomena, such as the enterohepatic cycle and incomplete absorption, were taken into account. Analog-hybrid simulation and identification represents an effective tool for such studies. In spite of the limited validity of the available in vivo data, the work represents a first step in the introduction of DHESN into human medicine.

Appropriate nitroxoline dosage regimen design.

Clinically used dosage regimen of nitroxoline, three times 100 mg daily, was proved to be inappropriate because the successfulness of medical treatment was rarely sufficient. Nitroxoline, used as urinary antiseptic, exhibits its antibacterial activity in concentrations higher than 6 mg/l, as demonstrated in many "in vitro" experiments. This work deals with the most appropriate nitroxoline dosage form as well as with the optimal dosage regimen design. The data were obtained by the aid of the suitable pharmacokinetic model and multiple dosing simulation on analog-hybrid computer EAI 580. From the several studied alternatives two usable dosage forms with the necessary dose and corresponding dosage interval were selected.

Clinical pharmacokinetics of nitroxoline.

14C-Nitroxoline was given orally to the rats, and its distribution as well as plasma and bile levels were determined autoradiographically and by the aid of radioactivity measurements, respectively. Nitroxoline was also given to the human volunteers orally and intravenously in three various doses and the corresponding urine concentrations of unconjugated and conjugated nitroxoline were determined spectrophotometrically. A pharmacokinetical model was generated on the basis of the results. The curve fitting procedure between total nitroxoline cumulative quantities in urine and the model response simulated on analog-hybrid computer enabled the evaluation of the validity of the chosen model as well as of the identification of its parameters.