Biomedical subjects

Chang-Koo Shim

Publications and source records attributed to Chang-Koo Shim.

At least 19 recordsLinked to original sources

PubMed2007

Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies.

Serially passaged normal human bronchial epithelial (NHBE) cell monolayers were established on Transwell inserts via an air-liquid interface (ALI) culture method. NHBE cells were seeded on polyester Transwell inserts, followed by an ALI culture from day 3, which resulted in peak TEER value of 766+/-154 Omegaxcm2 on the 8th day. Morphological characteristics were observed by light microscopy and SEM, while the formation of tight junctions was visualized by actin staining, and confirmed successful formation of a tight monolayer. The transepithelial permeability (Papp) of model drugs significantly increased with the increase of lipophilicity and showed a good linear relationship, which indicated that lipophilicity is an important factor in determining the Papp value. The expression of P-gp transporter in NHBE cell monolayers was confirmed by the significantly higher basolateral to apical permeability of rhodamine123 than that of reverse direction and RT-PCR of MDR1 mRNA. However, the symmetric transport of fexofenadine.HCl in this NHBE cell monolayers study seems to be due to the low expression of P-gp transporter and/or to its saturation with high concentration of fexofenadine.HCl. Thus, the development of tight junction and the expression of P-gp in the NHBE cell monolayers in this study imply that they could be a suitable in vitro model for evaluation of systemic drug absorption via airway delivery, and that they reflect in vivo condition better than P-gp over-expressed cell line models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Enhancing effect of surfactants on fexofenadine.HCl transport across the human nasal epithelial cell monolayer.

The effect of various surfactants (sodium cholate, sodium taurocholate, Tween 80 and Poloxamer F68) on enhancing the transepithelial permeability of fexofenadine.HCl was evaluated in a human nasal epithelial cell monolayer model. The cytotoxicity of the surfactants on the human nasal epithelial cells was evaluated by the MTT assay. A dose-dependent reduction of cell viability was observed at higher than critical micelle concentration (CMC) of the surfactants, and the IC50 of non-ionic surfactants (Tween 80 and Poloxamer F68) was higher than that of ionic surfactants (sodium cholate and sodium taurocholate). The TEER values significantly decreased after 2 h incubation with the ionic surfactants, but were recovered after 24 h in the fresh culture media. Ionic surfactants significantly increased the transepithelial permeability (P(app)) of fexofenadine.HCl compared to the non-ionic surfactants. The reduction of TEER values upon exposing the cell monolayer to the surfactants for 2 h correlated well with the P(app) of fexofenadine.HCl, which suggests that the permeation-enhancing mechanism of the ionic surfactants is by altering the tight junction property of the paracellular pathway. F-actin staining showed that the effect of ionic surfactants on the tight junction is temporary and reversible, which is consistent with the TEER value recovery within 24 h. These results imply that ionic surfactants are potentially useful permeation enhancers for nasal delivery of hydrophilic compounds, such as fexofenadine.HCl. This study also indicated the usefulness of the human nasal epithelial cell monolayer model not only for evaluating the in vitro nasal drug transport but also for studying the mechanism and toxicity of enhancers.

Cell Membrane Permeability↗

PubMed2006

Quantification of clotiazepam in human plasma by gas chromatography-mass spectrometry.

An analytical procedure was developed and validated for the quantification of clotiazepam in human plasma. After subjecting plasma samples to solid-phase extraction, the extract was evaporated and the residue re-constituted. An aliquot of the mixture was injected onto a gas chromatography-mass spectrometry system. The detector response was linear for clotiazepam concentrations in the range of 5-200 ng/ml. Intra- and inter-day precision for the assay over the concentration range was below 13.1 and 13.5%, and the accuracy ranged between 99.0-107.9% and 92.4-101.3%, respectively. The drug was found to be stable under various processing conditions used. The method is applicable to human pharmacokinetic studies of clotiazepam.

Azepines↗

PubMed2006

Clinical pharmacokinetics of oxaliplatin and 5-fluorouracil administered in combination with leucovorin in Korean patients with advanced colorectal cancer.

PURPOSE: Oxaliplatin and 5-fluorouracil (5-FU) act synergistically in colorectal cancer. Here, we evaluated the pharmacokinetics of oxaliplatin and 5-FU administered in combination with leucovorin in Korean advanced colorectal cancer patients. METHODS: Nine patients with advanced colorectal cancer were included in this study. The 3-week regimen consisted of oxaliplatin (2-h infusion, 130 mg/m(2)on day 1) followed by 5-FU and leucovorin (2-h infusion, 425 and 20 mg/m(2), respectively, from day 1 to day 5). Blood samples were taken and platinum concentrations in total plasma, plasma ultrafiltrate, and RBCs were determined. Plasma concentrations of 5-FU were also determined. RESULTS: The C (max) of oxaliplatin was observed at the end of infusion, with mean values of 4.66, 0.84, and 2.69 microg/ml for total plasma, plasma ultrafiltrate, and RBC samples, respectively. C (max) ratios of total/free were significantly higher than those reported in other ethnic groups. An accumulation of platinum was observed in RBCs, but not in total plasma and plasma ultrafiltrate samples. A significant correlation was found between the total body clearance of ultrafiltrable platinum and creatinine clearance. The C (max) of plasma 5-FU ranged from 23.9 to 533.8 ng/ml, indicating large inter-patient pharmacokinetic variations. CONCLUSIONS: This study shows that pharmacokinetics of oxaliplatin in Korean patients is comparable with that of other ethic groups, except for the higher C (max) ratios of total/free. The C (max) of 5-FU in plasma showed large variations among patients. Antitumor efficacy in Korean advanced colorectal cancer patients given oxaliplatin and 5-FU should be further evaluated with respect to pharmacokinetic variabilities.

Adenocarcinoma↗

PubMed2006

Mechanism of intestinal transport of an organic cation, tributylmethylammonium in Caco-2 cell monolayers.

Many quaternary ammonium salts are incompletely absorbed after their oral administration and may also be actively secreted into the intestine. However, the underlying mechanism(s) that control the transport of these cations across the intestinal epithelium is not well understood. In this study, the mechanism of absorption of quaternary ammonium salts was investigated using Caco-2 cell monolayers, a human colon carcinoma cell line. Tributylmethyl-ammonium (TBuMA) was used as a model quaternary ammonium salts. When TBuMA was administrated at a dose of 13.3 imole/kg via iv and oral routes, the AUC values were 783.7 +/- 43.6 and 249.1 +/- 28.0 micormole x min/L for iv and oral administration, indicating a lower oral bioavailability of TBuMA (35.6%). The apparent permeability across Caco-2 monolayers from the basal to the apical side was 1.3 times (p < 0.05) greater than that from the apical to the basal side, indicating a net secretion of TBuMA in the intestine. This secretion appeared to be responsible for the low oral bioavailability of the compound, probably mediated by p-gp (p-glycoprotein) located in the apical membrane. In addition, the uptake of TBuMA by the apical membrane showed a Na+ dependency. Thus, TBuMA appears to absorbed via a Na+ dependent carrier and is then secreted via p-gp related carriers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Altered pharmacokinetics and hepatic uptake of TBuMA in ethynylestradiol-induced cholestasis.

The objective of this study was to examine the pharmacokinetics of organic cations in intrahepatic cholestatic rats. A pretreatment with 17alpha-ethynylestradiol was used to induce intrahepatic cholestasis, and tributylmethylammonium (TBuMA) was used as a representative model organic cation. When [3H]TBuMA was intravenously administered1 the AUC value for TBuMA was significantly increased by 79% in cholestasis, and its total systemic clearance was consequently decreased by 46%. In addition, the in vivo hepatic uptake clearance of TBuMA from the plasma to the liver was decreased by 50% in cholestasis. The concentration of bile salts in plasma was increased by 2.1 fold in cholestatic rats. Since TBuMA forms ion-pair complexes with anionic components such as bile salts, the decreased hepatic uptake of TBuMA in cholestasis may be due to a change in endogenous components, e.g., bile salts in the plasma. In isolated normal hepatocytes, the uptake clearance for TBuMA in the presence of cholestatic plasma was decreased by 20% compared with normal plasma. Therefore, we conclude that the inhibition of the hepatic uptake process by the cholestasis may be in part due to the increased formation of ion-pair complexes of TBuMA with bile salts in the plasma.

Animals↗

PubMed2006

The transport of organic cations in the small intestine: current knowledge and emerging concepts.

A wide variety of drugs and endogenous bioactive amines are organic cations (OCs). Approximately 40% of all conventional drugs on the market are OCs. Thus, the transport of xenobiotics or endogenous OCs in the body has been a subject of considerable interest, since the discovery and cloning of a family of OC transporters, referred to as organic cation transporter (OCTs), and a new subfamily of OCTs, OCTNs, leading to the functional characterization of these transporters in various systems including oocytes and some cell lines. Organic cation transporters are critical in drug absorption, targeting, and disposition of a drug. In this review, the recent advances in the characterization of organic cation transporters and their distribution in the small intestine are discussed. The results of the in vitro transport studies of various OCs in the small intestine using techniques such as isolated brush-border membrane vesicles, Ussing chamber systems and Caco-2 cells are discussed, and in vivo knock-out animal studies are summarized. Such information is essential for predicting pharmacokinetics and pharmacodynamics and in the design and development of new cationic drugs. An understanding of the mechanisms that control the intestinal transport of OCs will clearly aid achieving desirable clinical outcomes.

Animals↗

PubMed2006

Application of a sample pooling method for the accelerated assessment of the rate of uptake of drugs by the brain in rats.

The purpose of this study was to examine the feasibility of applying a sample pooling method to the accelerated estimation of the uptake clearance of drugs to the brain in rats. Brain uptake clearances (CL(uptake)) were estimated for five model compounds using the sample pooling method and an integration plot analysis. CL(uptake) was also evaluated for caffeine and theophylline by brain microdialysis. The parameters and throughput of the pooling method were compared with those of typically used standard methods. The correlation for CL(uptake) was statistically significant (P<0.005) between the integration plot and the current method; the throughput of evaluation was 15-fold higher for the sample pooling method. A comparison of CL(uptake) values indicated that the three methods showed comparable results for caffeine while the CL(uptake) of theophylline using the proposed method was significantly different from those of the other methods. A kinetic analysis indicated that a compound with a slower CL(uptake) and longer half-life (e.g., theophylline) is more prone to error and that the lower limit of the CL(uptake) of 0.17 mL min(-1) (g brain)(-1) may be set so as to have an error less than 20% of the estimation. These results suggest that the sample pooling method is applicable for use in the accelerated estimation of the uptake clearance of compounds in the brain for which the value is greater than 0.17 mL min(-1) (g brain)(-1).

Animals↗

PubMed2005

Effect of nonylphenol ethoxylates (NPEs) on barrier functions of epithelial cell membranes: opening of tight junctions and competitive inhibition of P-gp-mediated efflux.

The effect of nonylphenol ethoxylates (NPEs) on selected barrier functions of biological membranes, such as tight junction and P-gp efflux pump of epithelial membranes, against the transport of xenobiotics was examined. The Caco-2 cell line was used to evaluate the transport of mannitol and daunomycin across the cell monolayer as well as the cellular uptake of daunomycin. In the presence of NPEs, the transport of mannitol was increased, with NP-9 showing a maximal effect, and the transepithelial electrical resistance (TEER) was reduced. The onset of this effect of NP-9 was fairly rapid and reversible for a short term (e.g., 2 h) treatment, while irreversible for a long term (e.g., 72 h) treatment. In the presence of NP-9, the apical uptake of daunomycin was increased, suggesting competitive inhibition between NP-9 and daunomycin in the efflux via the P-gp system. However, a 72 h pretreatment of the cells with NP-9 (up to 1000 nM) did not affect the apparent cellular uptake of daunomycin, suggesting no significant effect of NPEs on the expression of P-gp. In conclusion, NPEs appear to rapidly open the tight junction of epithelial cell membranes and to competitively inhibit the efflux of P-gp substrates, thereby reducing the self-protection ability of the organism against xenobiotics or hazardous environmental compounds that are transported via the paracellular pathway (i.e., uptake) or the P-gp system (i.e., efflux).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf.

Aqueous extracts from dried immature fruit of Poncirus trifoliata Raf. (Rutaceae) (PF-W) are used as a traditional Korean folk medicine for the treatment of digestive dysfunction. In the present study, PF-W exhibited no significant toxicity even at a dose of 5 g/kg when orally administered to mice. The effect of PF-W on gastrointestinal (GI) motor function was investigated by examining its effect on the serum concentration of orally administered ranitidine, a putative indicator of GI motility, in human subjects. The area under the serum concentration-time curve and the peak serum concentration of ranitidine following an oral administration (300 mg/individual) were decreased by one half as the result of a predose (10 g/individual) of PF-W, except for the time to reach peak serum concentration and the serum half-life at the terminal phase of ranitidine. In rat studies, PF-W had no effect on the apparent permeability of ranitidine across the jejunum or the gastric emptying rate (GER) of phenol red. However, the transit time for charcoal in the intestine was significantly increased by the PF-W pretreatment. The above results are consistent with the hypothesis that PF-W has a unique prokinetic activity, which accelerates the transit of intestinal contents, but has no effect on the GER.

Animals↗

PubMed2005

Effect of an aqueous extract of dried immature fruit of Poncirus trifoliata (L.) Raf. on intestinal transit in rodents with experimental gastrointestinal motility dysfunctions.

The effect of an aqueous extract of the dried immature fruit of Poncirus trifoliata Raf. (Rutaceae) (PF-W) on gastrointestinal (GI) motor function was investigated by measuring the intestinal transit rate (ITR) of Evans blue in rats and mice with experimental GI motility dysfunctions (GMDs). GMD was induced by appropriate surgery or by the administration of acetic acid, atropine, L-DOPA, or morphine to the animals. The ITR in these GMD animals was significantly retarded compared to normal animals. The retardation, however, was significantly inhibited by the intragastric administration of PF-W (0.1-1g/kg) in a dose dependent manner for all GMD models except for L-DOPA-induced GMD. The above results suggest that PF-W has the potential for development as a prokinetic agent that may prevent or alleviate GMD in human patients.

Animals↗

PubMed2005

Enhanced intestinal absorption of salmon calcitonin (sCT) from proliposomes containing bile salts.

PURPOSE: The feasibility of using proliposomes containing salmon calcitonin (sCT) and absorption enhancing agents, as an oral delivery system, to improve the intestinal absorption of sCT was explored using rats and Caco-2 cell systems. METHODS: Seventeen surfactants were examined for their effects with reference to accelerating the permeability of sCT (300 microg/ml) across Caco-2 cell monolayers, and damage to the intestinal epithelial cells, as measured by the change in transepithelial electrical resistance (TEER) across the cell monolayer. Proliposomes containing sCT (0.75%, w/w) and sodium taurodeoxycholate (NaTDC, 2.5%, w/w) (TDC proliposomes) were prepared according to the standard method using sorbitol and phosphatidylcholine as core and wall-forming materials, respectively, administered intra-duodenally to rats, and plasma concentrations of sCT were subsequently determined by LC-MS. RESULTS: Among the surfactants examined, some bile salts including NaTDC appeared to be the most advantageous when estimated based on the balance between the permeation enhancement (e.g., a 10.8-fold increase in the permeability of sCT for 0.1% NaTDC) and damage to the cells (e.g., a 3.55-fold decrease in the TEER value for 0.1% NaTDC). The administration of TDC proliposomes resulted in a 7.1-fold increase in the bioavailability (i.e., 0.49%) of sCT, when administered duodenally to rats. The size of the reconstituted liposomes in water was significantly smaller (e.g., 23.2 nm, number weighted diameter), and the entrapment efficiency (EE) of sCT in the reconstituted liposomes was 2.8-fold larger (54.9%), for TDC proliposomes, compared to proliposomes prepared without NaTDC (sCT proliposomes). CONCLUSION: A 7.1-fold increase in the bioavailability of sCT could be achieved from the TDC proliposomes. In addition to the intrinsic activity of the bile salt to fluidize the membrane, the simultaneous delivery of sCT and NaTDC to the site of absorption in the intestine via proliposomes and the subsequent formation of lipophilic ion-pair complexes between sCT and NaTDC at the site might have been contributing factors in this outstanding absorption enhancement.

Animals↗

PubMed2005

Mechanism of the stationary canalicular excretion of tributylmethyl ammonium in rats with a CCl4-induced acute hepatic injury.

The in vivo canalicular excretion clearance of tributylmethyl ammonium (TBuMA), a P-glycoprotein (P-gp) substrate, was previously reported to be unaffected by the induction of an experimental hepatic injury (EHI) by CCl(4) despite the increased expression of P-gp in the EHI liver. The objective of this study, therefore, was to elucidate the mechanism for the unchanged canalicular excretion clearance of TBuMA in EHI rats. TBuMA uptake was increased in cLPM vesicles from EHI rats compared with that from control rats. The total bile salt concentration in EHI liver was significantly reduced compared with that in a control liver. Because, in our previous studies, the uptake of TBuMA by cLPM vesicles was found to be significantly enhanced in the presence of bile salts, the reduction in bile salt levels in the EHI liver may be related to the unaltered TBuMA clearance. Despite the fact that the uptake of TBuMA by cLPM vesicles was increased by the addition of an EHI liver extract, the extent of the increase was comparatively less compared to the addition of a control liver extract. The in vivo excretion clearance of TBuMA was increased in a taurodeoxycholate dose-dependent manner in EHI rats. These observations suggest, therefore, that despite the induction of P-gp expression by the EHI, the in vivo canalicular excretion clearance of TBuMA remains unaltered as the result of an offset by reduced levels of bile salt(s).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Comparison of pharmacokinetics of loxoprofen and its active metabolites after an intravenous, intramuscular, and oral administration of loxoprofen in rats: evidence for extrahepatic metabolism.

The objective of this study was to characterize the extent of the formation of the active (trans-alcohol form) and inactive (cis-alcohol) metabolites of loxoprofen and to compare the kinetics after its intragastric, intravenous, and intramuscular administrations in rats. After intravenous administration of the drug at doses of 5-20 mg/kg, the clearance and the volume of distribution for loxoprofen, and the ratios of the AUC for the metabolites to the parent drug were not statistically different with the dosage; the formation clearances were 1.08 and 0.87 mL/min/kg for the active and its isomeric metabolite, respectively. After the intragastric, intravenous, or intramuscular administration, AUC for loxoprofen and the metabolites at a dose of 10 mg/kg were not statistically different for the different routes of administration. The formation of the metabolites with the concomitant loss of loxoprofen was found in incubations with liver homogenates and blood but not with a muscle homogenate or plasma, indicating that the conversion of loxoprofen to the metabolites may occur both in the liver and extraheptic tissue(s). Thus, approximately 22% of the loxoprofen may have been converted to the active metabolite in the liver and the extraheptic tissue(s) and the pharmacokinetics of the active metabolite was independent of the route of administration.

Administration, Oral↗

PubMed2005

Dose dependency in the oral bioavailability of an organic cation model, tributylmethyl ammonium (TBuMA), in rats: association with the saturation of efflux by the P-gp system on the apical membrane of the intestinal epithelium.

The oral bioavailability of tributylmethyl ammonium (TBuMA), an organic cation (OC), exhibited a dose-dependency (i.e., 17, 27, and 35% at doses of 0.4, 4, or 12 micromol/kg, respectively) in the rat. Relevant mechanisms were investigated in the present study by estimating the mucosal to serosal (m-s) and serosal to mucosal (s-m) transport of TBuMA across the rat ileum in an Ussing chamber experiment. The m-s permeability rapidly increased with TBuMA concentration in the mucosal side, and then becoming constant at high TBuMA concentrations. Various studies, including temperature- and potential-dependency and inhibition experiments, revealed that carrier-mediated transport mechanisms (most likely OCT1, OCT3, and P-gp) are involved in the s-m transport of TBuMA, and the saturation of the transport at higher concentrations is responsible for the concentration-dependency in the m-s permeability or dose-dependency of the bioavailability of TBuMA. A nonlinear regression of the m-s transport, based on the assumption of a mixed process of linear diffusion and saturable efflux, exhibited a clearance (CLlinear) of 0.343 microL/min/cm2 for the passive diffusion, and an apparent Km of 241 microM for the saturable process. The Km value is consistent with the concentration range in the intestine which is expected to be achieved after the oral dosing of TBuMA at a dose of 0.4 micromol/kg (i.e., 68 approximately 185 microM). Interestingly, the m-s transport of TBuMA was increased by the presence of P-gp substrates or inhibitors in the mucosal side, but not by the mucosal presence of OCT substrates or inhibitors, suggesting that only efflux transport systems on the apical membrane (e.g., P-gp), but not those on the serosal membrane (e.g., OCT1 and OCT3), of the intestinal epithelial cells, are involved in the dose-dependency or concentration dependency. A similar relationship seems likely for drugs that are substrates of efflux transporters on the apical membrane of the intestinal epithelium.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

Advanced formulation and pharmacological activity of hydrogel of the titrated extract of C. asiatica.

Titrated extract of Centella asiatica (TECA) contains three principal ingredients, asiaticoside (AS), asiatic acid (AA), and madecassic acid (MA). These components are known to be clinically effective on systemic scleroderma, abnormal scar formation, and keloids. However, one problem associated with administration of TECA is its low solubility in aqueous as well as oil medium. In this study, various nonionic surfactants and bile salts as anionic surfactant were tested and screened for solubilizing TECA with a view to developing topical hydrogel type of ointment which is stable physicochemically, and has better pharmacological effects. When TECA was incorporated into various nonionic surfactant systems, labrasol had the most potent capacity for solubilizing TECA. In cases of bile salt systems, Na-deoxycholate (Na-DOC) had foremost solubilizing capacity, even more than labrasol. In differential scanning calorimetric study, the peaks of AA, MA, AS and Na-DOC disappeared at the coprecipitate of 1% TECA and 1% Na-DOC, suggesting the optimum condition of Na-DOC for solubilizing TECA. When the physicochemical stability of hydrogel containing this mixture was assessed, it was stable at room temperature for at least one month. Pharmacologically it significantly decreased the size of wound area at the 9th day when applied to the wound area of rat dorsal skin. Taken together, solubility of TECA was dramatically improved by using nonionic and anionic surfactant systems, and Na-DOC was found to be the most effective solubilizer of TECA in formulating a TECA-containing hydrogel typed ointment. Moreover this gel was considered to be applicable to clinical use for wound healing effect.

Animals↗

PubMed2005

Transport of anti-allergic drugs across the passage cultured human nasal epithelial cell monolayer.

The purpose of this study was to investigate the nasal absorption characteristics of a series of anti-allergic drugs across the human nasal epithelial cell monolayer, which was passage cultured by the liquid-covered culture (LCC) method on Transwell. Characterization of this cell culture model was achieved by bioelectric measurements and morphological studies. The passages 2--4 of cell monolayers exhibited the TEER value of 1731+/-635 Omega cm(2) after 2 days of seeding and maintained high TEER value for 4--6 days. Morphological study by TEM and SEM showed the existence of the tight junctions, and the cuboidal shaped epithelial cells monolayer. A series of anti-allergic drugs, albuterol hemisulfate, albuterol, fexofenadine HCl, dexamethasone, triamcinolon acetonide, and budesonide were selected as model compounds for transport studies. All the drugs were assayed using reversed-phase HPLC under isocratic conditions. Results indicated that within the logP (apparent 1-octanol/water partition coefficient) range from --1.58 (albuterol) to 3.21 (budesonide), there existed 100-fold difference in the apparent permeability coefficients (P(app)). A log-linear relationship was shown between the drug logP and the P(app) across passaged human nasal epithelial monolayers. The amount of fexofenadine HCl and dexamethasone across passaged human nasal cell monolayers was concentration-dependent in the direction of apical to basolateral. The direction dependent transport studies were investigated among all these drugs and no significant difference in the two directions was observed. In conclusion, this LCC passaged human nasal epithelial culture model may be a useful in vitro model for studying the passive transport processes in nasal drug delivery.

Anti-Allergic Agents↗

PubMed2005

In vitro and in vivo evaluation of a novel nonscrotal matrix-type transdermal delivery system of testosterone.

A matrix-type testosterone (TS) transdermal delivery system for nonscrotal skin was developed with DuroTak 87-2510 as an adhesive polymer. When 3% dodecylamine was used in combination with 10% span 80, the in vitro rat permeation rate increased from 2.29 microg/cm2/hr to 6.51 microg/cm2/ hr as the TS loading dose increased from 2% to 6%. The maximum flux of experimental patch was about 14-fold higher than that of Testoderm. Release kinetics of TS from the patches was proportional to t1/2 following the Higuchi equation, and the release rate of TS increased as TS loading dose increased. Also, a good linear relationship between the skin permeation rate and the release rate was observed, which implies that the release rate is the rate-limiting process of the skin permeation. In vivo study showed that the plasma concentration of TS promptly increased and reached the peak level within 3-6 hours of application of the experimental patch. Area under the curve (AUC0 approximately 48) and Cmax also linearly increased in a dose-dependent manner up to 6% of TS. These results demonstrate the feasibility of developing a nonscrotal matrix-type transdermal delivery system of TS.

Administration, Cutaneous↗