RESUMEN

The bioavailability of rafoxanide was compared after intraruminal and intra-abomasal administration in healthy adult sheep (n = 6) in a single dose, 2 parallel group study at 7.5 mg/kg. Rafoxanide concentrations in plasma were measured by means of HPLC analysis. Primary pharmacokinetic parameters for bioavailability and disposition of rafoxanide in plasma for both routes of administration were determined by non-compartmental and non-linear, 1-compartmental pharmacokinetic analysis, respectively. Significantly (P < or = 0.05) higher peak plasma concentrations (c(max)) of rafoxanide and a more rapid rate of absorption (c. 3.5 times) was observed in sheep after intra-abomasal (i-a) administration compared to intraruminal (i.r.) administration. A significantly (P < or = 0.05) longer lag period (t(lag)) before absorption (6.8 +/- 2.9 h) occurred after i.r. than after i-a treatment (1.9 +/- 0.6 h). There was no significant difference (P > 0.05) in AUC, MRT and in the rates of elimination (k10-HL and t(1/2beta)) between the i.r. and i-a routes of administration. The results of the study demonstrated the important influence of the rumino-reticulum on absorption of rafoxanide in sheep.

Asunto(s)

RESUMEN

The plasma and salivary disposition of closantel and rafoxanide were examined following intravenous administration in adult sheep. Two studies were conducted with rafoxanide at 7.5 mg/kg and 1 with closantel using 2 doses (5 and 15 mg/kg). The pharmacokinetic profile of both drugs in plasma were best described by a 2-compartmental model with 1st-order rate constants. Plasma disposition of closantel and rafoxanide were characterised by a rapid distribution (t1/2(alpha)) of <30 min), long elimination half-life (t1/2(beta)) of 17.0 +/- 4.0 days for closantel and 7.2 +/- 0.6 days for rafoxanide), small apparent volume of distribution (V(SS) of <0.15 l/kg) and a slow rate of total body clearance (Cl of <0.01 ml/min/kg). The area under the drug plasma concentration curve (AUC) of closantel at 5 mg/kg was nearly twice as large as that of rafoxanide at 7.5 mg/kg resulting from the slower t1/2(beta) observed with closantel compared to rafoxanide. Large individual differences were observed in the rate measurements of distribution (k12, k21 and t1/2(alpha)), whereas the parameters of elimination (k10, t1/2(beta) and Cl), were more consistent between animals. A dose proportional increase in AUC was observed for closantel administered at 5 and 15 mg/kg. A low, constant salivary concentration of closantel (mean of 0.04 +/- 0.05 microg/mL) and rafoxanide (mean of 0.07 +/- 0.04 microg/mL) was observed during the 24-h examination period after dosing.

Asunto(s)

RESUMEN

Two new bioavailability parameters were recently suggested [Koeleman et al. 1991] to define (i) the time that the concentration in the blood stays above a defined minimum effective concentration, te and (ii) the onset of the effect, to. In addition to conventional bioequivalence parameters, the new bioavailabilty parameters (to and te) were calculated in this study and statistically compared for penicillin, chloroquine, oxytetracycline, amoxycillin and flucloxacillin from available bioequivalence data. For oxytetracycline, flucloxacillin and amoxycillin, the conventional bioavailability parameters indicated partial equivalence whereas using the te and to parameters, more realistic indications of the possible extent of the performance of a drug from dosage forms were obtained than with the conventional bioequivalence parameters. The new parameters gave additional information for a better evaluation of the performance of a drug from a dosage form.

Asunto(s)

RESUMEN

It is well known that food influences the absorption and therapeutic efficacy of many drugs. In this study, the influence of three different types of breakfast, on the absorption of paracetamol was studied in a South African ethnic population group (Tswanas). The results indicated that breakfasts with a high fat content delayed the absorption of paracetamol to the largest extent while breakfasts with a high carbohydrate content delayed the absorption of paracetamol to a lesser extent.

Asunto(s)

RESUMEN

Pharmacokinetic parameters such as AUC, Cmax and tmax have been used to represent the rate and extent of absorption of drugs from dosage forms in comparative bioequivalence testing. None of these parameters gives a direct indication of how long the drug concentration is maintained above an acceptable level e.g. minimum inhibitory concentration (MIC) or the minimum effective concentration (MEC). This is clinically important in evaluating the onset and duration of a therapeutic effect obtained from a test dosage form in comparison to the reference dosage form. The purpose of this study is to investigate the possibility of a bioavailability parameter which relates the time that the drug concentration in the systemic circulation is maintained above a certain level (te) and the first time that the blood concentration exceeds this level (to). Two methods were used to calculate the time that drug levels are maintained above a certain minimum level. The proposed parameters proved to be valuable when the efficacy of erythromycin was used as an example. Although some problems, such as undefined MIC/MEC may arise, te and to can be used along with the conventional bioequivalence parameters to obtain a better indication of the clinical efficacy.

Asunto(s)

RESUMEN

Since most bioavailability studies are usually done with only a limited number of volunteers (usually 10-30), the statistical properties of the calculated bioavailability parameters are not well defined. The established statistical methods to test bioequivalence are usually based on either the assumption of normality or a symmetrical distribution. However, the decision of which method to apply, depends primarily on the distributional assumption of the data. In this study, an approach is followed where the small data base of a limited number of volunteers is expanded by adding pseudo-volunteers by "bootstrap" simulations. From such a larger data base it is easier to determine the statistical distributional properties of bioavailability parameters, which in its turn leads to the identification of an appropriate statistical method. With more certainty on which statistical method to apply, the original data can be used more effectively in testing for bioequivalence. In this paper, comparisons are made between the distributions of bioavailability parameters of an actual 60-volunteer study and those of two simulated data sets. Each such data set contained a random sample of 10 volunteers each (from the 60 volunteers), together with 50 pseudo-volunteers. These 50 volunteers were simulated from the random sample of 10 real volunteers. Good correspondences were obtained when comparing these two data sets with the original data, which indicated the validity to use this approach in bioavailability studies where a small number of volunteers had been used. This method proved useful to define the distributional properties for a relative small number of parameter-values available.

Asunto(s)

Asunto(s)

Asunto(s)