Tenoxicam pharmacokinetics in rats: a population model.

This study was designed to establish the in vivo relationship between tenoxicam disposition and changes in plasma protein binding measured as an unbound fraction in plasma (fu). Tenoxicam was administered as a bolus 5-mg/kg dose, and total plasma concentrations, plasma albumin percentage, and fu were examined in five groups of rats (uremia or anephric states were experimentally induced in four groups to decrease plasma protein levels). Albumin levels were significantly decreased in all experimentally altered groups with respect to control animals (p < 0.01). A two-compartment population pharmacokinetic model that includes the effect of fu on the kinetic parameters was proposed to describe tenoxicam plasma concentration profiles. Plasma clearance (CL) increased but not proportionally with fu. Apparent volume of distribution of the central compartment (V) was linearly related to changes in fu and intercompartmental clearance was not affected by altered plasma protein binding. Expressing pharmacokinetic parameters as a function of fu resulted in a three- and five-fold decrease in the variability associated with CL and V, respectively.

Pharmacokinetics of thymoxamine in rabbits after ophthalmic and intravenous administration.

The pharmacokinetics of thymoxamine hydrochloride were studied in rabbits by the assessment of its ocular and systemic absorption after instillation of thymoxamine hydrochloride 0.5% eye drops. Plasma levels were compared with those observed after i.v. bolus administration of thymoxamine hydrochloride at 2.5 mg/kg. Deacetylthymoxamine is the main metabolite of thymoxamine, generated by esterase hydrolysis. It was evaluated, as an indication of the parent drug, in aqueous humor and plasma by an HPLC method with fluorescence detection (detection limit = 5 ng/ml). Thymoxamine was found to permeate the cornea and to be hydrolysed very quickly, showing very good absorption with a maximum aqueous humor concentration of deacetylthymoxamine of 2329 ng/ml 15 min after eye drop instillation. The study of the systemic absorption of thymoxamine allowed the exclusion of the possibility of systemic side effects following ocular treatment. In fact, considering the detection limit of the method, the plasma levels of deacetylthymoxamine are certainly more than 100-times lower than those observed with intravenous treatment.

Tenoxicam: acute dose-dependent disposition studies in rats.

Single intravenous bolus doses of tenoxicam of 2.5, 5, and 10 mg/kg were administered to male Wistar rats to determine the effects of dose on tenoxicam pharmacokinetics. Predicted apparent volume of distribution at steady state (Vdss) and total plasma clearance (CL) were, respectively, 42 and 45% higher in the animals given 10-mg/kg dose than the animals given 2.5- and 5-mg/kg doses. Binding of tenoxicam to plasma proteins showed saturability, with a 33% higher unbound fraction of tenoxicam in plasma when total drug concentration in plasma was 36 mg/L (high dose group) in comparison with animals given the low doses (12 and 20 mg/L). The blood-to-plasma concentration ratio of tenoxicam was concentration independent and therefore did not account for the observed dose-dependent changes in Vdss and CL.

High-performance liquid chromatographic analysis of piroxicam and tenoxicam in plasma, blood and buffer solution. Application to pharmacokinetic studies in small laboratory animals.

A rapid and sensitive high-performance liquid chromatographic procedure is described for the simultaneous determination of piroxicam (CAS 36322-90-4) and tenoxicam (CAS 59804-37-4) in blood, plasma and buffer solutions used in the equilibrium dialysis studies. The method can be used to measure either piroxicam and tenoxicam in these three fluids using the other as internal standard. A Nucleosil C18 and a mobile phase consisting of an acetonitrile-distilled water-acetic acid (58 : 38 : 4) mixture were used. The flow rate was 1 ml/min and the effluent was monitored at 365 nm with 0.02 AUFS (absorbance units full scale). The sensitivities of this method were 0.2 microgram/ml levels of piroxicam and tenoxicam in the plasma, blood and buffer solutions samples.

Effect of induced hypoalbuminemia on distribution, total clearance and unbound clearance of piroxicam in vivo in the rat.

The influence of decreased albumin concentration on the pharmacokinetic behaviour of Piroxicam was studied in vivo in rats that had undergone plasmapheresis. Reductions of approximately 25% and 50% in the plasma albumin concentration were achieved, the former in rats not given plasma expander, the latter in animals given Ficol-70 as a plasma expander. The unbound fraction of Piroxicam in plasma and the apparent volume of distribution at steady state experienced a statistically significant increase where the albumin concentration was reduced. The average total plasma clearance rose with the increase in fu, between the control (6.3 +/- 2.4 ml/h) and plasmapheretic groups (11.1 +/- 4 ml/h), in accordance with predictions of the 'well-stirred' and 'parallel-tube' models, but no statistically significant differences were found between the two groups, perhaps because of the great interindividual variability associated with this parameter. The total plasma clearance value of the Ficol group (5.4 +/- 2.2 ml/h) was close to that of the control group, despite the high increase in the unbound fraction in plasma. Alterations in the uptake process in the liver due to the high level of induced hypoalbuminemia may have occurred.

Residence time distribution of diazepam in the isolated perfused rat liver. Analysis with the axial dispersion model.

The application of the axial dispersion model to diazepam hepatic elimination was evaluated using data obtained for impulse-response experiments with diazepam in the single-pass isolated perfused rat liver preparation. The transient form of the two-compartment dispersion model was applied to the output concentration versus time profile of diazepam after bolus input of a radiolabelled tracer into the hepatic portal vein (n = 4), providing DN and CLint estimates of 0.251 +/- 0.093 and 135 +/- 59 ml min-1, respectively. In contrast, the one-compartment form of the axial dispersion model, which assumes instantaneous transversal distribution of substance to the accessible spaces within the liver, could not adequately describe the residence time distribution (RTD) of diazepam. Furthermore, the magnitude of DN, a stochastic parameter which characterizes the axial spreading of solutes during transit through the liver, is similar to that determined for non-eliminated substances such as erythrocytes, albumin, sucrose and water. These findings suggest that the dispersion of diazepam in the perfused rat liver is determined primarily by the architecture of the hepatic microvasculature.

Effect of uraemia and anephric state on the pharmacokinetics of tenoxicam in the rat.

Renal alterations, uraemia and nephrotic syndrome induced in experimental animals caused a reduction in the plasma albumin concentration of 25 and 30%, respectively. As a result of this decrease, the unbound fraction of tenoxicam in uraemic rats (0.06 +/- 0.02) and in anephric rats (0.11 +/- 0.08) increased with respect to the control group (0.03 +/- 0.004). The induced hypoalbuminaemia did not modify the blood to plasma concentration ratio. Both plasma clearance (CL) and apparent volume of distribution at steady-state (Vdss) rose significantly with the increase in the unbound fraction: (Vdss 55 +/- 6 mL (control rats); 69 +/- 12 mL (uraemic rats); 96 +/- 30 mL (anephric rats); CL = 7 +/- 1 mL h-1 (control rats); 12 +/- 4 mL h-1 (uraemic rats); 15 +/- 7 mL h-1 (anephric rats)). Tenoxicam elimination was found to be restrictive, with an extraction ratio less than 0.1 in the three groups. The induction of nephrotic syndrome was observed to have a significant effect on intrinsic metabolic activity, intrinsic clearance of tenoxicam being reduced by 30% in the anephric rats (161 +/- 38 mL h-1) with respect to the values obtained in the control group (228 +/- 22 mL h-1).

Ocular pharmacokinetics of thiamphenicol in rabbits.

The ocular pharmacokinetics of thiamphenicol (TAP, CAS 15318-45-3) was studied in rabbits by means of the assessment of its ocular and systemic absorption, and urinary excretion after instillation of 0.5% TAP eye drops. TAP concentrations in aqueous humor, plasma and urine were evaluated by a coupled LC/GC method (detection limit = 0.1 ng/ml), because the necessity to have a technique much more sensitive than the traditional chromatographic ones available in order to quantify the very low drug concentrations in biological fluids produced by the ocular treatment, and generally by a topical administration. The intravenous route was chosen as reference and allowed the absolute bioavailability to be estimated. TAP proved to be well absorbed through the cornea with the peak aqueous humor concentration of 110 ng/ml at 45 min following the instillation. The good ocular absorption of TAP was confirmed by the plasma concentrations observed after instillation of 0.5% eye drops. In any case, these concentrations were more than 1000 times lower than those observed after the intravenous treatment at the dose normally used for infectious diseases, allowing to exclude any systemic toxicity of TAP eye drops. The absolute ocular bioavailability was 16.2% when estimated from the AUC values and 34.0% from the cumulative urinary excretion values.

Role of surfactants in the bioavailability of intranasal insulin.

The nasal mucosa has good physiological characteristics to allow the administration through other routes presents some problems, such is the case of insulin. The presence of surfactants is necessary to get high bioavailability.

Pharmacokinetic profiles of prazepam and 14C-prazepam in rat.

Pharmacokinetics of Prazepam and 14C-Prazepam were studied in rat. Prazepam was measured in blood and plasma by a gas-liquid chromatography assay with an electron capture detector. Its major metabolite, Desmethyldiazepam, was also determined in blood in the same way. Total radioactivity was measured in plasma by scintillation spectrometry. Pharmacokinetic analysis were carried out by two ways; according to compartmental pharmacokinetic models and by statistic moments.

Pharmacokinetics of piroxicam in rats.

Pharmacokinetic of piroxicam was studied in the rat. Plasma and blood samples were analyzed by an high-performance liquid chromatography assay method. Plasma protein binding and blood to plasma concentration ratio were determined. Pharmacokinetic analysis was carried out fitting exponential equation to experimental data. All calculations were made using both JANA and PCNONLIN programs. This study reports a good estimation of the pharmacokinetic parameters of piroxicam in rats.

Comparative diltiazem plasma clearance in normotensive and hypertensive rats.

Diltiazem plasma clearance was studied in normotensive (NR) and spontaneous hypertensive rats (SHR), either following intravenous bolus administration of 3 mg/kg (CLiv), or after 25 min of intravenous infusion (CL25) at different dose levels (1, 2, 4, and 8 mg/kg/30 min in NR; 0.5, 1, 2, and 4 mg/kg/30 min in SHR). The diltiazem pharmacokinetic profile fit a two-compartment open model better, both in NR and SHR. The CLiv of diltiazem was significantly higher in NR than in SHR. Following infusion, diltiazem plasma clearance increased for high levels of infused dose in NR and in SHR. For each level of dose, CI25 was significantly higher in NR than in SHR. For both groups of animals, CI25 values were significantly higher than their respective CIiv values. These results show the influence of hypertension on the pharmacokinetic characteristics of diltiazem, as well as the effect of its own vasodilator action. An increase in diltiazem clearance values may be due to an increase in hepatic blood flow that is a result of its vasodilator action.

Kinetics of pharmacological effect of diltiazem in spontaneous hypertensive rats.

The kinetics of intravenous (i.v.) infusion of diltiazem was studied in spontaneous hypertensive rats (SHR) at three dose levels (1, 2 and 4 mg/kg/30 min). Apparent clearance values (Cle) were obtained from the decline of diltiazem hypotensive effect through a model based on the relationship R vs. log dose. For each dose level there were no significant differences between apparent Cle values and real Cl values obtained from plasmatic concentrations at 25 min after infusion (Cl25). However, for both groups of data, Cl values increased with dose. For each level of perfused dose, Cl25 values were significantly higher than clearance values obtained after i.v. bolus administration of 3 mg/kg (Cliv).