• Journal of Pharmaceutical Investigation
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• 제40권6호
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• pp.321-332
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• 2010

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the "passage" culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

• Biomolecules & Therapeutics
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• 제15권2호
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• pp.102-107
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• 2007

Cimetidine, a substrate for P-glycoprotein (P-gp), is a well known drug interacting with a variety of drugs and results in alteration of pharmacokinetic parameters by concomitant administration. The aim of present study was to investigate whether cimetidine affects the transport of various quinolone antibiotics in human colorectal cancer cell line (Caco-2) system which has been typically used to investigate drug transport via P-gp. The apparent permeability coefficients (P$_{app}$) value of 9 quinolone antibiotics in the co-treatment with cimetidine was examined. Apical to basolateral (AP-to-BL) transport of fleroxacin in the co-treatment with cimetidine was increased to 1.5-fold (p<0.01) compared with that of fleroxacin alone, whereas basolateral to apical (BL-to-AP) transport of fleroxacin was decreased to 0.83-fold significantly (p<0.05). Ofloxacin was decreased to 0.8-fold (p<0.01) and 0.72-fold (p<0.01) significantly in AP-to-BL and BL-to-AP direction, respectively by cimetidine cotreatment. The P$_{app}$ values of gatifloxacin, moxifloxacin, ciprofloxacin and rufloxacin also were changed by cimetidine. These results have a potential that cimetidine influences on the pharmacokinetics of quinolone antibiotics. It suggests that careful drug monitoring and dosage adjustment may be necessary during the co-administration of quinolone antibiotics with cimetidine.

• Journal of Pharmaceutical Investigation
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• 제26권1호
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• pp.43-53
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• 1996

The objective of this study was to determine whether 4-phenylazobezyloxycarbonyl-Pro-Leu-Gly-Pro-D-Arg (Pz-peptide), an enhancer of hydrophilic solute permeability in the intestine, could elevate the paracellular permeability of hydrophilic drugs across cornea and conjunctiva in the rabbit. The in-vitro penetration of hydrophilic drugs (mannitol, atenolol) and lipophilic drug (propranolol) across the rabbit cornea and conjunctiva was studied either in the presence or absence of 3 mM Pz-peptide. Drug penetration was evaluated using the modified Ussing chamber. The conjunctiva was more permeable than the cornea to all drugs. Pz-peptide showed enhanced effects on the drug transport across cornea and conjunctiva in a concentration dependent manner. Effects or ion transport inhibitor on the mannitol penetration were then investigated. Mannitol penetration was not changed by serosal addition of $100\;{\mu}M$ ouabain, suggesting that $Na^+/K^+$ ion tranporter was not involved in the Pz-peptide induced elevation of paracellular drug permeability. Furthermore, effects of Pz-peptide and EDTA on the transport of atenolol and propranolol into the ocular tissues or blood circulation after its administration into both eyes were investigated. EDTA showed enhanced effect on propranolol transport into the ocular tissues, but Pz-peptide did not show significant difference. Systemic absorption of propranolol by the addition of EDTA or Pz-peptide was not changed. On the other hand, EDTA and Pz-peptide elavated the atenolol transport into the ocular tissues. The transport of atenolol into the blood circulation was also enhanced by the addition of EDTA, but no effect was observed by the addition of Pz-peptide. The above findings suggest that Pz-peptide would be used as an paracellular pathway enahncer of hydrophilic drugs into the eye, without affecting the systemic absortion of topically applied opthalmic drugs.

• Journal of Pharmaceutical Investigation
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• 제31권4호
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• pp.273-279
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• 2001

The purpose of this study is to characterize the iontophoretic transport of growth hormone releasing peptides (GHRP-6) through hairless mouse skin from aqueous solution. The effect of various factors, such as pH, poloarity, current profile, current density, current duration, ionic strength, drug concentration, and enhancer application was studied to obtain basic knowledge on the transport. We have also studied the stability of GHRP-6 in solution with/without current. The donor chamber was filled with phosphate buffer solution containing GHRP-6 and the receptor chamber was filled with phosphate buffer solution (pH 7.4). Ag/AgCl electrode was used for their stability and reversibility. At a predetermined time interval, sampling was made and the concentration of drug was analysed using HPLC system. The results showed that, compared to passive flux, the total amount of drug transported increased markedly by the application of anodal current. Cathodal flux was similar to passive flux. Flux increased with the current density, the duration of current application and drug concentration. The effect of enhancers on the flux was studied using hydrophilic (5% N-methyl pyrrolidone) and hydrophobic (5% propylene glycol monolaurate, 5% oleic acid) enhancers. Application of enhancer also increased the flux.

• Journal of Pharmaceutical Investigation
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• 제34권4호
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• pp.275-281
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• 2004

We have studied the effect of polarity, current density, current duration, crosslinking density, swelling ratio, and permeation enhancers on the transdermal flux of ketoprofen from acrylamide hydrogel. Hydrogel was prepared by free radical crosslinking polymerization of acrylamide. Drug loading was made just before transport experiment by soaking the hydrogel in solution containing drug. In vitro flux study using hairless mouse skin was performed at $36.5^{\circ}C$ using side-by-side diffusion cell, and the drug was analysed using HPLC/UV system. The result showed that, compared to passive flux, the total amount of drug transported increased about 18 folds by the application of $0.4\;mA/cm^2$ cathodal current. Anodal delivery with same current density also increased the total amount of drug transported about 13 folds. It seemed that the increase in flux was due to the electrorepulsion and the increase in passive permeability of the skin by the current application. Flux increased as current density, the duration of current application and loading amount (swelling duration) increased. As the cross linking density of the hydrogel increased, flux clearly decreased. The effect of hydrophilic enhancers (urea, N-methyl pyrrolidone, Tween 20) and some hydrophobic enhancers (propylene glycol monolaurate and isopropyl myristate) was minimal. However, about 3 folds increase in flux was observed when 5% oleic acid was used. Overall, these results provide some useful information on the design of an optimized iontophoretic delivery system of ketoprofen.

• Journal of Pharmaceutical Investigation
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• 제32권1호
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• pp.21-26
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• 2002

The primary culture of human nasal epithelial cell monolayer was performed on a Transwell. The effect of various factors on the tight junction formation was observed in order to develop an in vitro experimental system for nasal transport studies. Human nasal epithelial cells, collected from human normal inferior turbinates, were plated onto diverse inserts. After 4 days, media of the apical surface was removed for air-liquid interface (ALI) culture. Morphological characteristics was observed by transmission electron microscopy (TEM). A polyester membrane of $0.4\;{\mu}m$ pore size was determined as the most effective insert based on the change in the transepithelial electric resistance (TEER) value as well as the $^{14}C-mannitol$ transport study. The ALI method was effective in developing the tight junction as observed in the further increase in the TEER value and reduction in the permeability coefficient $(P_{app})$ of $^{14}C-mannitol$ transport. Results of the transport study of a model drug, budesonide, showed that the primary culture system developed in this study could be further developed and applied for in vitro nasal transport studies.

• Archives of Pharmacal Research
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• 제18권3호
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• pp.141-145
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• 1995

Omeprazole, a proton pump inhibitor, was given intravenously (iv), orally (po), intraperitoneally (ip), hepatoportalvenously (pv), and intrarectally (ir) to rats at a dose of 72mg/kg in order to investigate the bioavailability of the drug, The extent of bioavailabilities of omeprazole administered through pv, ip, po, and ir routes were 88.5, 79.4, 40,8, and 38.7%, respectively. Pharmacokinetic analysis in this study and literatures (Regardh et al., 1985 : Watanabe et al., 1994) implied significant dose-dependency in hepatic first-pass metabolism, clearance and distribution, and acidic degradation in gastric fluid. The high bioavailability from the pv administration (88.5%) means that only 11.5% of dose was extracted by the first-pass metabolism through the liver at this dose (72 mg/kg). The low bioavailability from the oral administration (40.8%) in spite of minor hepatic first-pass extraction indicates low transport of the drug from GI lumen to portal vein. From the literature (Pilbrant and Cederberg, 1985), acidic degradation in gastric fluid was considered to be the major cause of the low transport. Thus, enteric coating of oral preparations would enhance the oral bioavailability substantially. The bioavailability of the drug from the rectal route, in which acidic degradation and hepatic first-pass metabolism may not occur, was low (38.7%) but comparable to that from the oral route (40.8 %) indicating poor transport across the rectal membrane. In this case, addition of an appropriate absorption enhancer would improve the bioavailability. Rectal route seems to be an possible alternative to the conventional oral route for omeprazole administration.

• Biomolecules & Therapeutics
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• 제25권4호
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• pp.441-451
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• 2017

Imperatorin, a major bioactive furanocoumarin with multifunctions, can be used for treating neurodegenerative diseases. In this study, we investigated the characteristics of imperatorin transport in the brain. Experiments of the present study were designed to study imperatorin transport across the blood-brain barrier both in vivo and in vitro. In vivo study was performed in rats using single intravenous injection and in situ carotid artery perfusion technique. Conditionally immortalized rat brain capillary endothelial cells were as an in vitro model of blood-brain barrier to examine the transport mechanism of imperatorin. Brain distribution volume of imperatorin was about 6 fold greater than that of sucrose, suggesting that the transport of imperatorin was through the blood-brain barrier in physiological state. Both in vivo and in vitro imperatorin transport studies demonstrated that imperatorin could be transported in a concentration-dependent manner with high affinity. Imperatorin uptake was dependent on proton gradient in an opposite direction. It was significantly reduced by pretreatment with sodium azide. However, its uptake was not inhibited by replacing extracellular sodium with potassium or N-methylglucamine. The uptake of imperatorin was inhibited by various cationic compounds, but not inhibited by TEA, choline and organic anion substances. Transfection of plasma membrane monoamine transporter, organic cation transporter 2 and organic cation/carnitine transporter 2/1 siRNA failed to alter imperatorin transport in brain capillary endothelial cells. Especially, tramadol, clonidine and pyrilamine inhibited the uptake of [$^3H$]imperatorin competitively. Therefore, imperatorin is actively transported from blood to brain across the blood-brain barrier by passive and carrier-mediated transporter.

• Archives of Pharmacal Research
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• 제2권1호
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• pp.65-70
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• 1979

Distribution and binding properties of sodium salicylate the human red blood cells were studied under various experimental conditions. The effect of tonicity and hemolysis on the steady state level of the drug within the human red blood cells were accounted for in this study. When the washed cells were suspended in normal saline solution, the drug was so rapidly permeated into red cells. Since the pH of the system forces nearly complete ionization of the drug, ionic diffusion through aqueous pores is thought to be the mode of salicylate transport. Human red cell binding capacity and association constant for salicylate were estimated. This work supports the view that the red cells act asan important reservior of salicylate.

• Genomics & Informatics
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• 제19권4호
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• pp.39.1-39.8
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• 2021

Tamoxifen (TAM) is an anticancer drug used to treat estrogen receptor (ER)-positive breast cancer. However, its ER-independent cytotoxic and antifungal activities have prompted debates on its mechanism of action. To achieve a better understanding of the ER-independent antifungal action mechanisms of TAM, we systematically identified TAM-sensitive genes through microarray screening of the heterozygous gene deletion library in fission yeast (Schizosaccharomyces pombe). Secondary confirmation was followed by a spotting assay, finally yielding 13 TAM-sensitive genes under the drug-induced haploinsufficient condition. For these 13 TAM-sensitive genes, we conducted a comparative analysis of their Gene Ontology (GO) 'biological process' terms identified from other genome-wide screenings of the budding yeast deletion library and the MCF7 breast cancer cell line. Several TAM-sensitive genes overlapped between the yeast strains and MCF7 in GO terms including 'cell cycle' (cdc2, rik1, pas1, and leo1), 'signaling' (sck2, oga1, and cki3), and 'vesicle-mediated transport' (SPCC126.08c, vps54, sec72, and tvp15), suggesting their roles in the ER-independent cytotoxic effects of TAM. We recently reported that the cki3 gene with the 'signaling' GO term was related to the ER-independent antifungal action mechanisms of TAM in yeast. In this study, we report that haploinsufficiency of the essential vps54 gene, which encodes the GARP complex subunit, significantly aggravated TAM sensitivity and led to an enlarged vesicle structure in comparison with the SP286 control strain. These results strongly suggest that the vesicle-mediated transport process might be another action mechanism of the ER-independent antifungal or cytotoxic effects of TAM.