• Journal of Pharmaceutical Investigation
• /
• 제20권4호
• /
• pp.223-228
• /
• 1990

The contribution of endogenous transport systems to the blood-brain barrier (BBB) transport of basic and acidic drugs was studied by using a carotid injection technique in rats and an isolated bovine cerebrovascular disease state were compared between the normotensive rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) which have been well established as an animal model with pathogenic similarities to humans. Basic drugs such as eperisone, thiamine and scopolamine inhibited, in a concentration dependent manner the in vivo uptake of $[{^3}H]choline$ through BBB, whereas amino acids and acidic drugs such as salicylic acid and valproic acid did not inhibit the uptake. The uptake of $[^3H]choline$ by B-CAP increased with time and showed a remarkable temperature dependency. The uptake of $[^3H]choline$ by B-CAP showed the very similar inhibitory effects as observed in the in vivo brain uptake, and was competitively inhibited by a basic drug, eperisone. The in vivo BBB uptakes of $[^3H]acetic$ acid and $[^{14}C]salicylic$ acid were dependent on pH of the injectate and the concentration of drugs. Several acidic drugs such such as salicylic acid, benzoic acid and valproic acid inhibited the in vivo uptake of $[^3H]acetic$ acid, whereas amino acid, choline and a basic drug such as eperisone did not inhibit the uptake. The uptake of acetic acid by B-CAP was competitively inhibited by salicylic acid. The permeability surface area product (PS) through BBB for $[^3H]choline$ in SHRSP was significantly lower than that in WKY. The concentration of choline in the brain dialysate in SHRSP was about half of that in WKY, while no significant difference was observed in the plasma concentration of choline between SHRSP and WKY. No significant difference was observed in the transport of monocarboxylic acids, glucose and neutral amino acid through BBB between SHRSP and WKY. From these results, it was concluded that BBB transport system of choline contributes to the transport of basic drugs through BBB, that acidic drugs can be transported via a moncarboxylic acid BBB transport system and that the specific dysfuntion of the BBB choline transport in SHRSP was ascribed to the reduction of the maximum velocity of choline concentration in the brain interstitial fluids.

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

• Toxicological Research
• /
• 제23권1호
• /
• pp.1-9
• /
• 2007

Transporters are membrane proteins that mediate the transfer of substrate across the cellular membrane. In this overview, the characteristics and the toxicological relevance were discussed for various types of transporters. For drug transporters, the overview focused on ATP-binding cassette transporters and solute carrier family 21A/22A member transporters. Except for OCTN transporters and OATP transporters, drug transporters tend to have broad substrate specificity, suggesting drug-drug interaction at the level of transport processes (e.g., interaction between methotrexate and non-steroidal anti-inflammatory agents) is likely. For metal transporters, transporters for zinc, copper and multiple metals were discussed in this overview. These metal transporters have comparatively narrow substrate specificity, except for multiple metal transporters, suggesting that inter-substrate interaction at the level of transport is less likely. In contrast, the expressions of the transporters are often regulated by their substrates, suggesting cellular adaptation mechanism exists for these transporters. The drug-drug interactions in drug transporters and the cellular adaptation mechanisms for metal transporters are likely to lead to alterations in pharmacokinetics and cellular metal homeostasis, which may be linked to the development of toxicity. Therefore, the transporter-mediated alterations may have toxicological relevance.

• The Korean Journal of Physiology
• /
• 제10권1호
• /
• pp.35-40
• /
• 1976

In an attempt to examine the effect of ginseng on sodium transport across the biological membrane, we have studied effects of ginseng alcohol extract on the short-circuit current(SCC) and the $Na^+-K^+$-activated ATPase activity in isolated frog skin preparations. 1. Ginseng alcohol extract applied to the mucosal surface of the frog skin significantly increased SCC at low concentration($1{\sim}10mg%$) but decreased SCC at higher concentration($50{\sim}250mg%$). 2. Similarly, when the drug was added to the serosal bathing medium, the SCC was stimulated at low doses($5{\sim}25mg%$) and inhibibited at high doses($50{\sim}250mg%$). 3. $Na^+-K^+$-activated ATPase activity of the frog skin epidermal homogenate was significantly inhibited by ginseng alcohol extract, the effect being proportional to the concentration of the drug in the incubation mixture. These results may suggest that a low dose of ginseng alcohol extrat enhances the transepithelial sodium transport probably by increasing the permeability of outer membrane of the transporting cell to sodium ion, whereas a high dose of drug reduces the sodium transport primarly by inhibiting $Na^+-K^+$ ATPase mediated active transport step.

• 한국생물물리학회:학술대회논문집
• /
• 한국생물물리학회 1997년도 학술발표회
• /
• pp.21-21
• /
• 1997

Transport of drug entrapped in a liposome-hydrogel formulation was significantly retarded in an in vitro topical application. Liposomes containing hydrocortisone acetate, a hydrophobic antiinflammatory agent, were prepared by the precipitation method, and the liposomal suspension was mixed with hydrogel into a semisolid gel-type ointment.(omitted)

• Biomolecules & Therapeutics
• /
• 제30권1호
• /
• pp.1-18
• /
• 2022

Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.

• 생물정신의학
• /
• 제7권1호
• /
• pp.21-33
• /
• 2000

As the clinical practice of using more than one drug at a time increase, the clinician is faced with ever-increasing number of potential drug interactions. Although many interactions have little clinical significances, some may interfere with treatment or even be life-threatening. This review provides a better understanding of drug-drug interactions often encountered in pharmacotherapy of depression. Drug interactions can be grouped into two principal subdivisions : pharmacokinetic and pharmacodynamic. These subgroups serve to focus attention on possible sites of interaction as a drug moves from the site of administration and absorption to its site of action. Pharmacokinetic processes are those that include transport to and from the receptor site and consist of absorption, distribution on body tissue, plasma protein binding, metabolism, and excretion. Pharmacodynamic interactions occur at biologically active sites. In this review, emphasis is placed on antidepressant medications, how they are metabolized by the P450 system, and how they alter the metabolism of other drugs. When prescribing antidepressant medications, the clinician must consider the drug-drug interactions that are potentially problematic.

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

• The Korean Journal of Physiology
• /
• 제10권1호
• /
• pp.1-5
• /
• 1976

The trypanocidal drug suramin, an impermeant polyanion, has been shown to be a powerful inhibitor of the calcium uptake and calcium-stimulated ATPase activity of sarcoplasmic reticulum (Fortes et al., 1974). In view of this finding, an attempt was made to investigate the effect of suramin on $Ca^{++}$ transport in resealed red cells and on $Ca^{++}$-activated ATPase in red blood cell membrane fragments (RBCMF). The results obtained are summarized as follows. 1. $Ca^{++}$ outflux from the resealed RBC was inhibited by suramin and the inhibitory action of suramin is proportional to the concentration of drug added inside the RBC preparation. When suramin is added both inside and outside the RBC preparation simultaneously, the magnitude of the inhibitory effect was more pronounced, suggesting that suramin inhibits both active $Ca^{++}-^{45}Ca$ exchange diffusion across the RBC membrane. 2. Suramin inhibits the $Ca^{++}$-activated ATPase of the RBCMF and the effect of inhibition by the drug was also concentration dependent. From the above results, it may be concluded that suramin inhibits $Ca^{++}$ transport across RBC membrane by inhibiting $Ca^{++}$-activated ATPase activity which has been known to be linked with active $Ca^{++}$ transport.

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