Electrically enhanced transdermal delivery of a macromolecule

The purpose of this study was to establish the delivery parameters for the enhanced transdermal delivery of dextran sulfate (MW 5000 Da). Full-thickness pig skin or epidermis separated from human cadaver skin was used. Silver-silver chloride electrodes were used to deliver the current (0.5 mA cm-2). For electroporation experiments, one or more pulses were given using an exponential decay pulse generator. The correct polarity for iontophoresis and pulsing was first established as cathode in the donor. The amount of drug delivered increased with increasing donor concentration up to a point, but not any further. The amount delivered also increased with pulse voltage, the delivery being twice as much as with iontophoresis alone (144.5+/-10.35 microg cm(-2)), when 6 pulses of 500 V were applied at time zero before iontophoresis (276+/-45.2 microg cm(-2)). It was observed that the amount delivered was a function of increasing pulse length when the apparent charge delivered was kept constant. Transport through pig skin (107.4+/-24.4 microg cm(-2)) was found to be comparable with that through human epidermis (84.9+/-18.4 microg cm(-2)). In conclusion, we have demonstrated the transdermal delivery of a 5000 Da molecular weight dextran sulfate using iontophoresis. It was also seen that iontophoretic delivery could be enhanced by simultaneous electroporation.     

Effect of electroporation and iontophoresis on skin permeation of Defibrase--a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov

The purpose of this study was to investigate electroporation and iontophoresis as a means for in vitro delivery of Defibrase--a thrombin-like enzyme (TLE) from Agkistrodon halys ussuriensis Emelianov snake venom--through human epidermis membrane (HEM). Electroporation was carried out using an exponential decay pulse generator (BioR-ad Genepulser, USA) for a period of 0.5 h, followed by a period of 5.5 h passive diffusion or iontophoresis. The results indicated that the combined use of electroporation and anodal iontophoresis in pH 6.4 permeation medium could effectively enhance the skin permeation of Defibrase, whose apparent permeability coefficient was 1.6 +/- 0.8 x 10(-4) cm.h-1. The delivery of Defibrase by the combined use of electroporation and anodal iontophoresis was more effective than by electroporation alone (P < 0.01) or by the combined use of electroporation and cathodal iontophoresis (P < 0.01). Moreover, when the pH of the permeation medium was raised from 6.4 to 7.4 the permeation of Defibrase caused by a combined use of electroporation and anodal iontophoresis showed a tendency to increase. These results implied that electroosmotic flow effect might be important for the iontophoretic (following electroporation) skin permeation of Defibrase.     

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34)

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34), hPTH (1-34), was investigated in vitro, using dermatomed porcine skin. The effect of iontophoretic current density, electroporative pulse voltages and also electroporation followed by iontophoresis was investigated on the in vitro percutaneous absorption of hPTH (1-34). Iontophoresis at 0.5 mA/cm2 current density significantly enhanced (P<0.05) the flux of hPTH (1-34) in comparison to passive flux. Electroporation pulses of 100, 200 and 300 V significantly increased (P<0.05) the flux of hPTH (1-34) in comparison with the passive as well as iontophoretic flux at 0.5 mA/cm2. The electroporative flux of hPTH (1-34) was found to vary linearly (R2 = 0.97) with the pulse amplitude. The principal barrier of the skin, stratum corneum, was found perturbed following the pulses as evident by light microscopy studies. The application of electroporation pulses followed by iontophoresis further increased the flux by several fold. The flux of hPTH (1-34) with the electroporation pulses of 100 and 300 V followed by iontophoresis at 0.2 mA/cm2 was 10- and 5-fold higher, respectively, in comparison to the flux with corresponding pulses alone. This shows the synergistic effect of iontophoresis in combination with electroporation on skin permeability of hPTH (1-34). The results indicate the possibility of designing controlled transdermal delivery systems for hPTH (1-34) using electroporation followed by iontophoresis.     

Transdermal Iontophoresis of Rotigotine Across Human Stratum Corneum in Vitro: Influence of pH and NaCl Concentration

PURPOSE: The aim of this study was to characterize the influence of pH and NaCl concentration on the transdermal iontophoretic transport of the dopamine receptor agonist rotigotine across human stratum corneum (HSC). METHODS: Rotigotine transport was studied in vitro in side by side diffusion cells according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis, and 5 h of passive diffusion. A current density of 0.5 mA cm(-2) was used. The influence of donor phase pH (4, 5, and 6) and different concentrations of NaCl (0.07 and 0.14 M) on rotigotine iontophoretic flux were examined. The acceptor phase was phosphate-buffered saline (PBS) at pH 7.4 except in one series of experiments aimed to study the effects of rotigotine solubility on its iontophoretic transport. In this study, PBS at pH 6.2 was used. In separate studies. 14C-mannitol was used as a marker to determine the role of electro-osmosis during iontophoresis. RESULTS: The estimated iontophoretic steady-state flux (Flux(ss)) of rotigotine was influenced by the pH of the donor solution. At a drug donor concentration of 0.5 mg ml(-1), the iontophoretic flux was 30.0 +/- 4.2 nmol cm(-2) h(-1) at pH 6 vs. 22.7 +/- 5.5 nmol cm(-2) h(-1) at pH 5. However, when the donor concentration was increased to 1.4 mg ml(-1), no significant difference in iontophoretic rotigotine transport was observed between pH 5 and 6. Increase of NaCl concentration from 0.07 M to 0.14 M resulted in a decrease of the rotigotine Flux(ss) from 22.7 +/- 5.5 nmol cm(-2) h(-1) to 14.1 +/- 4.9 nmol cm(-2) h(-1). The contribution of electro-osmosis was estimated less than 17%. Probably due to the lipophilic character of the drug, impeding the partitioning of rotigotine from HSC to the acceptor compartment, steady-state transport was not achieved during 9 h of iontophoresis. CONCLUSIONS: Both pH and NaCl concentration of the donor phase are crucial on the iontophoretic transport of rotigotine. Electro-repulsion is the main mechanism of the iontophoretic transport of rotigotine.     

Post-iontophoresis transport of ibuprofen lysine across rabbit ear skin

The aim of this work was to study in vitro the post-iontophoresis transport of ibuprofen lysine across rabbit ear skin, from ibuprofen lysine water solutions (20-200 mg/ml and pH 6.8-7.8). Current densities of 0.125, 0.25, and 0.5 mA/cm(2) were applied either continuously or for 15, 30, and 60 min followed by passive diffusion for up to 5h. The results showed a significantly higher cathodal transport compared to passive flux. Anodal iontophoresis also increased ibuprofen permeation, even though the drug is negatively charged. The application of an electric current for a limited period of time, followed by passive diffusion from the reservoir in contact with the skin, produced much higher post-iontophoresis fluxes of ibuprofen than passive diffusion. Post-iontophoresis transport of ibuprofen from lysine salt solutions linearly depended on the total amount of current applied during iontophoresis, and in the absence of background ions was independent of donor drug concentration. The reason for this behavior was the creation of a drug reservoir in the skin owing to the short period of current application.     

Effect of Electroporation on Transdermal lontophoretic Delivery of Luteinizing Hormone Releasing Hormone (LHRH) in Vitro

Electroporation, the creation of transient, enhanced membrane permeability using short duration (microseconds to millisecond) electrical pulses, can be used to increase transdermal drug delivery. The effect of an (electroporative) electric pulse (1000 V, = 5 msec) on the iontophoretic transport of LHRH through human skin was studied in vitro. Fluxes achieved with and without a pulse under different current densities (0- 4 mA/cm²) were compared. The results indicated that the application of a single pulse prior to iontophoresis consistently yielded higher fluxes (5—10 times the corresponding iontophoretic flux). For example, at 0.5 mA/cm² fluxes were 0.27 ± 0.08 and 1.62 ± 0.05 µg/hr/cm² without and with the pulse, respectively. At each current density studied, the LHRH flux decreased after iontophoresis, approaching pre-treatment values. The results show that electroporation can significantly and reversibly increase the flux of LHRH through human skin. These results also indicate the therapeutic utility of using electroporation for enhanced transdermal transport.     

电致孔和离子导入对胰岛素经皮渗透的促进作用

目的研究电致孔(EP)和离子导入(ION)对胰岛素经皮渗透的影响。方法以水平双室扩散池的方法,研究电致孔与离子导入联合应用对胰岛素经皮渗透的促进作用,并与单独使用离子导入或电致孔进行比较。结果 电致孔与离子导入联用比单独离子导入显著增加胰岛素的经皮渗透性(P<0.05),且高电压比低电压电致孔离子导入显著增加胰岛素的渗透速率(P<0.01)。胰岛素离子导入前,500 V电压,给90次脉冲(指数衰减脉冲,每次脉冲持续时间20～24 ms,3次·min^-1),导致了透皮流速(Flux)的快速稳定增加。结论电致孔和离子导入联用能明显促进大分子胰岛素的经皮渗透性。     

Pharmacokinetic and local tissue disposition of [14C]sodium diclofenac following iontophoresis and systemic administration in rabbits.

The systemic pharmacokinetics and local drug distribution of sodium diclofenac in skin and underlying tissues was studied. Iontophoresis facilitated local and systemic delivery of diclofenac sodium compared with passive diffusion. The maximum plasma concentration of sodium diclofenac was achieved within 1 h of iontophoresis, and the delivery was proportional to applied current density (371 +/- 141 and 132 +/- 62 microg/L at 0.5 and 0.2 mA/cm(2), respectively). The in vivo delivery efficiency for diclofenac in rabbit was 0.15 mg/mA.h. The concentrations of sodium diclofenac in the skin, subcutaneous tissue, and muscle beneath the drug application site (cathode) were significantly greater than plasma concentrations and concentrations of drug in similar tissues at the untreated sites. The results thus suggest that the cutaneous microvasculature is not always a perfect "sink" and that transdermal iontophoresis facilitated the direct penetration of diclofenac sodium to deeper tissues. No skin irritation was observed up to 0.5 mA/cm(2) current density and 7 mg/mL sodium diclofenac concentration.     

Gene expression and antitumor effect following imelectroporation delivery of human interferon α2 gene

AIM: To investigate the gene expression and antitumor effect following im electroporation delivery of human interferon alpha 2 (hIFN-alpha 2) gene. METHODS: The pcD2/hIFN-alpha 2 was injected into the middle of the quadriceps muscle of female BALB/c mice or the leukemia-bearing female BALB/c nude mice, and then electroporation was given to the injection site. Optimal electrical parameters and the efficiency of gene transfer was studied with hIFN-alpha 2 ELISA kit. The HL-60 tumor model in BALB/c nude mice was used to investigate therapeutic effects of im electroporation delivery of pcD2/hIFN-alpha 2. RESULTS: The optimal conditions for the electric pulses were as follows: voltage at 200 V/cm; pulse duration at 40 ms per pulse; number of pulse at 6 pulses and frequency at 1 Hz. Under optimal conditions, the serum hIFN-alpha 2 levels in electroporation group (160 microg/L+/-31 microg/L) were 45-fold higher than those of nonelectroporation group (3.6 microg/L+/-1.6 microg/L, P<0.01). The growth of leukemia was inhibited more obviously and the survival time of the leukemia-bearing nude mice was prolonged after im electroporation delivery of pcD2/hIFN-alpha 2 100 microg or 200 microg. CONCLUSION: Electroporation was an efficient method for the delivery of plasmid DNA and im electroporation delivery of pcD2/hIFN-alpha 2 was effective in treating leukemia.     

Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis

The purpose of this study was to investigate the effect of chemical enhancers (fatty acids and limonene) and iontophoresis on the in vitro permeability enhancement of insulin through porcine epidermis. The following fatty acids were used: palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3). Franz diffusion cells and the Scepter iontophoretic power source were used for the percutaneous absorption studies. Cathodal iontophoresis was performed at 0.2 mA/cm2 current density. Iontophoresis in combination with chemical enhancers synergistically increased (p<0.05) the in vitro permeability of insulin. Linolenic acid (C18:3) produced greater permeability of insulin through epidermis than did other fatty acids during passive (44.45 x 10(-4) cm/h) and iontophoretic (78.03 x 10(-4) cm/h) transport. Lispro insulin flux was significantly (p<0.05) greater through linolenic acid and limonene pretreated epidermis compared to untreated controls during both passive and iontophoretic transports. Using limonene as a penetration enhancer, a linear increase in the passive and iontophoretic flux of lispro insulin was observed with donor concentrations increasing from 100 IU/mL to 300 IU/mL. Iontophoretic flux through limonene-treated epidermis using 0.5 mA/cm2 current density and 300 IU/mL insulin donor solution was 45.63 IU/cm2/day. Using an iontophoretic patch size of 10 cm2, we would be able to deliver 50 IU of insulin within 3 h.     

Effect of sodium dodecyl sulfate on iontophoresis of hydrocortisone across hairless mouse skin

The purpose of the present work was to study the effect of sodium dodecyl sulfate (SDS), an anionic surfactant, on the iontophoretic transport of a neutral drug hydrocortisone (HC) across hairless mouse skin. The transport studies were conducted using Side-Bi-Side diffusion apparatus and drug concentration in the receptor cell was analyzed using reversed-phase HPLC. A theoretical model was described, tested, and found to agree well with experimental data (R2 = 0.9766). Anodal iontophoresis significantly enhanced the transport of HC compared to cathodal iontophoresis and passive diffusion, suggesting that the transport of the neutral solute occurs via the electro-osmotic flow. The effect of SDS on the transport of HC was highly concentration-dependent and driving mode-dependent. Below the critical micelle concentration (cmc), increasing the concentration of SDS increased both the passive and the iontophoretic fluxes of HC, but the increase was most significant with anodal iontophoresis. Above the cmc, passive transport of HC continued to increase with an increase in the SDS concentration. The transport after anodal iontophoresis, however, reached a plateau and then leveled off. Further increase in SDS concentration decreased flux, suggesting that the transport of micellar-solubilized drug is retarded by anodal iontophoresis, possibly due to electrostatic attraction.     

Localization of a FITC-Labeled Phosphorothioate Oligodeoxynucleotide in the Skin After Topical Delivery by Iontophoresis and Electroporation

Purpose. The aim of this study was to verify the hypothesis that the application of high voltage to the skin enhances both stratum corneum and keratinocyte permeability. Therefore, the transport of FITC labelled phosphorothioate oligonucleotides (FITC-PS) administered by passive diffusion, iontophoresis or electroporation was localized. Methods. Fluorescent microscopy and laser scanning confocal microscopy were used to visualize the FITC-PS transport at the tissue and cell level respectively in hairless rat skin after electroporation (5 × (200 V 500 ms) or iontophoresis (same amount of charges transferred). Results. FITC-PS did not penetrate the viable skin by passive diffusion. Molecular transport in the skin upon electroporation or iontophoresis was localized and implied mainly hair follicles for iontophoresis. In the stratum corneum, the pathways for FITC-PS transport were more transcellular during electroporation and paracellular during iontophoresis. FITC-PS were detected in the nucleus of the keratinocytes a few minutes after pulsing. In contrast, iontophoresis did not lead to an uptake of the oligomer. Conclusions. The internalization of FITC-PS in the keratinocytes after electroporation confirms the hypothesis and suggests that electroporation, which allows both efficient topical delivery and rapid cellular uptake of the oligonucleotides, might be useful for antisense therapy of epidermal diseases.     

Iontophoretic enhancement of leuprolide acetate by fatty acids, limonene, and depilatory lotions through porcine epidermis

The effect of chemical enhancers (e.g., fatty acids, limonene, depilatory lotions) and iontophoresis was investigated on the in vitro permeability of leuprolide acetate through porcine epidermis. Franz diffusion cells and Scepter iontophoretic power source were used for the percutaneous absorption studies. Anodal iontophoresis was performed at 0.2 mA/cm2 current density. Fatty acids used were palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3) acids. The passive and iontophoretic flux were significantly (p < 0.05) greater through fatty acids-treated porcine epidermis in comparison to the control (untreated epidermis) for leuprolide acetate. The passive and iontophoretic permeability of leuprolide acetate increased with increasing number of cis double bonds. Among the fatty acids tested, linolenic acid (C18:3) exhibited the maximum permeability of leuprolide acetate during passive (51.42 x 10(-4) cm/hr) and iontophoretic (318.98 x 10(-4) cm/hr) transport. The passive and iontophoretic flux of leuprolide acetate were significantly (p < 0.05) greater through the limonene and depilatory lotion treated epidermis in comparison to their respective control. In conclusion, iontophoresis in combination with chemical enhancers synergistically increased (p < 0.05) the in vitro permeability of leuprolide acetate through porcine epidermis.     

The effects of iontophoresis and electroporation on transdermal delivery of buprenorphine from solutions and hydrogels

The in-vitro permeation of buprenorphine across skin was investigated to assess the effects of iontophoresis and electroporation on drug permeation from solutions as well as from hydrogels. Iontophoresis (0.3 mA cm(-2)) increased the buprenorphine permeation from solution by a factor of 14.27 as compared with passive diffusion; the application of electroporation increased the buprenorphine permeation from solutions by a factor of 8.45. The permeation experiments using cellulose membrane and stratum corneum (SC)-stripped skin as permeation barriers suggested that the enhancement with iontophoresis was primarily due to strong electrophoretic drift of buprenorphine molecules, whereas the enhancement seen with electroporation was mainly attributed to the creation of transient aqueous pores in the SC layer. Application of high-voltage pulses followed by iontophoresis resulted in a shorter permeation onset time from both solutions and hydrogels as compared with iontophoresis or electroporation alone. The charge repulsion between buprenorphine and chitosan vehicles as well as the competition effects of counter-ions for carboxymethylcellulose (CMC)-based polymers may account for the different permeation rates under electrical field. This study demonstrates the feasibility of using hydrogels for delivery of buprenorphine under the application of iontophoresis or electroporation, separately or together.     

Effect of Sodium Dodecyl Sulfate on Iontophoresis of Hydrocortisone Across Hairless Mouse Skin

The purpose of the present work was to study the effect of sodium dodecyl sulfate (SDS), an anionic surfactant, on the iontophoretic transport of a neutral drug hydrocortisone (HC) across hairless mouse skin. The transport studies were conducted using Side-Bi-Side diffusion apparatus and drug concentration in the receptor cell was analyzed using reversed-phase HPLC. A theoretical model was described, tested, and found to agree well with experimental data (R² = 0.9766). Anodal iontophoresis significantly enhanced the transport of HC compared to cathodal iontophoresis and passive diffusion, suggesting that the transport of the neutral solute occurs via the electro-osmotic flow. The effect of SDS on the transport of HC was highly concentration-dependent and driving mode-dependent. Below the critical micelle concentration (cmc), increasing the concentration of SDS increased both the passive and the iontophoretic fluxes of HC, but the increase was most significant with anodal iontophoresis. Above the cmc, passive transport of HC continued to increase with an increase in the SDS concentration. The transport after anodal iontophoresis, however, reached a plateau and then leveled off. Further increase in SDS concentration decreased flux, suggesting that the transport of micellar-solubilized drug is retarded by anodal iontophoresis, possibly due to electrostatic attraction.     

Combined effects of iontophoretic and chemical enhancement on drug delivery. II. Transport across human and murine skin

This paper reports measurements of the release characteristics of the model drug salbutamol from a liquid crystalline vehicle across both human and hairless murine skin in vitro. The use of oleic acid and iontophoresis as penetration enhancement techniques, used separately and simultaneously, was also investigated. Over a period of 12h, salbutamol base did not diffuse from the vehicle across excised human skin while, in contrast, over a period of 2h, the drug passively transported across hairless murine skin. The diffusion co-efficient for the drug in this tissue was estimated to be 4.54+/-0.60x10(-9)cm(2)s(-1) with a permeability co-efficient of 7.03+/-0.83x10(-7)cms(-1). A current of density of 0.39mAcm(-2) facilitated a significant transport of salbutamol from the liquid crystalline vehicle across excised human skin but with a small (<0.1) transport number. The quantity of salbutamol transported across excised hairless murine skin under the same conditions was significantly greater with a transport number of 0.68. The alteration of the permeability of the tissue was less than that of the human skin and a full recovery of the pre-iontophoretic permeability of murine skin was consistently observed. The incorporation of either oleic or lauric acid into the monoglyceride component of the vehicle at a concentration of 0.1M had a marked effect on the transport of salbutamol across both human and murine skin. The initial passive permeation of the drug across the skin was not affected but the rate of drug delivery during iontophoresis was typically observed to increase by a factor greater than two. The post-iontophoretic transport of salbutamol across either tissue was also substantially enhanced in the presence of the fatty acid. The analogous use of stearic acid did not significantly influence the iontophoretic or the post-iontophoretic transport of salbutamol across excised human skin. The investigation also revealed a synergistic combination of the fatty acid and anodal iontophoresis to enhance the in vitro transport of other drug substances, including nicotine and diltiazem hydrochloride across murine skin. Oleic acid increased both the iontophoretic and post-iontophoretic transport of nicotine, so that the enhancement of drug delivery was greater than that caused by the current alone. The investigation also indicated that the barrier properties of the skin recover following the constant current iontophoresis in the presence of oleic or lauric acids.     

Electrically Modulated Transdermal Delivery of Fentanyl

Purpose. Test to determine if iontophoresis and electroporation, alone or in combination, can be used for rapid and modulated delivery of fentanyl. Methods. Fentanyl citrate (5 mg/ml) dissolved in pH 4.0 citrate buffer was delivered in vitro across human epidermis. For iontophoresis, a current of 0.5 mA/cm² was applied for 5 h, using silver/silver chloride electrodes. Electroporation protocol consisted of applying 15 exponential pulses of 500V (applied voltage) and 200 msec duration at the rate of 1 pulse per minute at time zero and, in some cases, repeating at 1.5 and 2.5 h. Results. There was no measurable permeation of fentanyl through human epidermis under passive conditions. A significant flux (about 80 g/cm²-hr) was achieved using iontophoresis and decreased once the current was turned off. A 4-fold higher flux and shorter lag time was observed with electroporation as compared to iontophoresis. The flux was found to recover quickly (within 1 h) following pulsing. Modulation of transdermal delivery of fentanyl was demonstrated by both iontophoresis and electroporation. Conclusions. Electrically assisted transdermal delivery of fentanyl significantly increased transport compared to passive delivery. Also, rapid and modulated delivery was shown to be feasible by programming the electrical parameters.     

Enhancement of Transdermal Iontophoretic Delivery of a Liposomal Formulation of Colchicine by Electroporation

Iontophoresis of colchicine solution through electroporated skin showed maximum enhancement as compared to iontophoresis and electroporation alone. Encapsulation of colchicine in positively charged liposomes further augmented the delivery,with the amount of drug in the receptor after 24 h being 1348 342 mug/cm2 when iontophoresis was performed through electroporated skin as compared to 666 38mug/cm2 when it was performed through nonelectroporated skin and 41 18mug/cm2 when only electroporation was performed. The impedance of the skin was observed to drop sharply due to electroporation, with a postpulse recovery of about 30% over 24h. Also the total amount transported was compared to the total charge delivered in the case of each of the protocols. Hence this serves as initial evidence for potential of charged liposomes for the enhanced transdermal delivery of nonionized or neutral drugs using a combination of electroporation and iontophoresis.     

Enhancement of Transdermal Iontophoretic Delivery of a Liposomal Formulation of Colchicine by Electroporation

Iontophoresis of colchicine solution through electroporated skin showed maximum enhancement as compared to iontophoresis and electroporation alone. Encapsulation of colchicine in positively charged liposomes further augmented the delivery,with the amount of drug in the receptor after 24 h being 1348 342 mug/cm2 when iontophoresis was performed through electroporated skin as compared to 666 38mug/cm2 when it was performed through nonelectroporated skin and 41 18mug/cm2 when only electroporation was performed. The impedance of the skin was observed to drop sharply due to electroporation, with a postpulse recovery of about 30% over 24h. Also the total amount transported was compared to the total charge delivered in the case of each of the protocols. Hence this serves as initial evidence for potential of charged liposomes for the enhanced transdermal delivery of nonionized or neutral drugs using a combination of electroporation and iontophoresis.     

Toxicokinetics and metabolism of N-[(14)C]N-methyl-2-pyrrolidone in male Sprague-Dawley rats: in vivo and in vitro percutaneous absorption.

Neat N-methyl-2-pyrrolidone (NMP) rapidly penetrated into the skin of male Sprague-Dawley rats after in vivo and in vitro topical application. At the two topical doses tested in vivo, no steady state was observed. The maximal absorption fluxes were 10 and 20 mg/cm(2)/h for 20 microl/cm(2) and 40 microl/cm(2), respectively. Similar results were observed after in vitro topical application of neat [(14)C]NMP (25-400 microl/cm(2)) in fresh full-thickness skin. Whatever the dose tested, the percutaneous absorption fluxes increased with exposure time to reach a maximum value (F(max)) and then decreased. F(max) and the time to reach it (T(max)) increased as the dose increased. At the highest dose, which may be considered as an "infinite dose," the maximal flux (7.7 +/- 1.1 mg/cm(2)/h, n = 12) occurred 6 h after the topical application of NMP. The decrease on percutaneous absorption flux was correlated with the dilution of neat NMP with water from the receptor fluid. A semi-quantitative mathematical model was developed to describe the absorption flux of NMP taking into account the transfer of water through the skin. The K(p) values determined from the different aqueous solutions of NMP (1:1 to 1:32, v/v) were not significantly different. The mean value was 6.4 (10(-3) cm/h) (range, 4.7 to 7.6). Occlusion did not affect the percutaneous absorption flux of neat NMP. Desquamation increased the percutaneous absorption of NMP slightly. The skin did not metabolize NMP. The flux was dependent on the thickness of the skin and was proportional to the concentration of NMP. These findings suggest a passive diffusion of NMP through the skin.