C. Peraire

Influence of d-limonene on the transdermal penetration of felodipine

SummaryFelodipine is a calcium antagonist, one of the dihydropyridines, with potential application in transdermal therapeutic systems (TTS). Earlier studies reported that the high lag time of this drug limited its potential development in a TTS. The present study analyzes the effect of d-limonene at concentrations of 0.5, 1, 5 and 10% on the transdermal penetration of this drug. The study was performed using a diffusion technique in vitro, with the skin of the hairless rat. d-Limonene significantly reduced the lag time (T1) to 1.4 h at a concentration of 1% (compared with 9.8 h in its absence). Higher concentrations did not produce a significant decrease in the value of this parameter. The presence of d-limonene in the formulae produces an increase in the permeability constant (Kp) and the flux (J). The relation between this increase and the percentage of d-limonene was non-linear. An asymptotic value was obtained at a concentration of 5%, with increases of 993% and 1570% for Kp and J, respectively.

Pharmacokinetics of cyanamide in dog and rat.

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague‐Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg−1, produced a dose‐dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12·6 to 19·7 mL kg−1 min−1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg−1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg−1) had a half life of 30 min, a total plasma clearance of 117 mL kg−1 min−1 and a mean residence time of 26 min. Oral bioavailability was about 69%.

Estimation of Transdermal Permeation Parameters in Non-stationary Diffusion Experiments. Application to Pre-treatment Studies with Terpenes

No HeadingPurpose.To estimate the applicability of transdermal drug permeation parameters in a finite-dose model for skin pre-treated with terpenes and to evaluate the enhancing effect of some terpene formulations on alprazolam permeation.Methods.In vitro enhancement of alprazolam human skin permeation was investigated using a pre-treatment with different terpene solutions. Vertical diffusion, Franz-type cells were used. Intrinsic drug permeation was also investigated. Transdermal permeation parameters were estimated from the per-meation tabulates using different theoretical approaches for their calculation. Two groups of permeation parameters were calculated: modelistic (diffusion of a finite-dose of drug model) and parameters non-dependent of a diffusional model.Results.In control experiments, all approaches of data treatment satisfactorily described the experimental permeation profiles. When skin pre-treatment was investigated, the fitting of a mathematical sigmoid function was much better than the diffusional approach. Pre-treatment of the skin with Limonene dissolved in ethanol / propylene glycol and Menthol dissolved in propylene glycol increased 15 and 10 times respectively the permeation parameters of alprazolam.Conclusions.Using enhancers that are rapidly cleared from the skin, skin permeability does not remain constant during the permeation experiment and therefore it is not possible to calculate parameters that are usually true coefficients or definite values. In this case, non-modelistic parameters can be used to estimate an enhancing effect.

Absolute Bioavailability and Absorption Profile of Cyanamide in Man

AbstractA pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L · kg−1· min−1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg

A Comparative In Vitro Study of Transdermal Absorption of a Series of Calcium Channel Antagonists

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Multiple dose pharmacokinetic study of cicletanine in healthy volunteers.

± SEM values of Cmax, tmax(median) and AUC were 0.18 ± 0.03, 0.91 ± 0.11, and 1.65 ± 0.27 μg · ml−1; 13.5, 13.5, and 12 min; and 8.59 ± 1.32, 45.39 ± 1.62, and 77.86 ± 17.49 μg · ml−1· min, respectively. Absorption was not complete and the oral bioavailability, 45.55 ± 9.22, 70.12 ± 4.73, and 80.78 ± 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis–Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg iv and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis–Menten kinetics, suggesting the presence of a saturable first-pass effect.

Reduction of oral bioavailability of paracetamol by tolmetin in rat.

According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 μg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 μg/cm(2)/μg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice.