• Biomolecules & Therapeutics
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• 제19권4호
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• pp.498-503
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• 2011

The purpose of this study was to investigate the effects of nisoldipine on the pharmacokinetics of repaglinide in rats. The effect of nisoldipine on cytochrome P450 (CYP) 3A4 activity and P-glycoprotein (P-gp) were evaluated. The pharmacokinetic parameters of repaglinide were also determined in rats after oral (0.5 $mg{\cdot}kg^{-1}$) and intravenous (0.2 $mg{\cdot}kg^{-1}$) administration of repaglinide to rats without or with nisoldipine (0.3 and 1.0 $mg{\cdot}kg^{-1}$). Nisoldipine inhibited CYP3A4 enzyme activity with a 50% inhibition concentration of 5.5 ${\mu}M$. In addition, nisoldipine significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, nisoldipine significantly increased the $AUC_{0-{\infty}}$ and the $C_{max}$ of repaglinide by 46.9% and 24.9%, respectively. Nisoldipine also increased the absolute bioavailability (A.B.) of repaglinide by 47.0% compared to the oral control group. Moreover, the relative bioavailability (R.B.) of repaglinide was 1.16- to 1.47-fold greater than that of the control group. Nisoldipine enhanced the oral bioavailability of repaglinide, which may be attributable to the inhibition of the CYP3A4-mediated metabolism in the small intestine and/or in the liver and to inhibition of P-gp in the small intestine rather than to reduction of renal elimination of repaglinide by nisoldipine. The increase in the oral bioavailability of repaglinide should be taken into consideration of potential drug interactions when co-administering repaglinide and nisoldipine.

• Journal of Pharmaceutical Investigation
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• 제20권1호
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• pp.1-5
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• 1990

Effect of an angiotensin inhibitor (AAS; loading dose of 25, 50, $100{\mu}g/kg$ and maintenance dose of 12.5, 25,$50{\mu}g/ka/hr$) on the pharmacokinetics of propranolol (4 mg/kg i.v.) was studied in rabbits. Plasma concentrations and relative bioavailability of propranolal increased upto 127-175% by AAS coinjection. The urinary excretion of propranolol decreased by AAS. Dosage regimen of propranolol should be adjusted when it is administered with AAS.

• 수면정신생리
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• 제19권1호
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• pp.18-21
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• 2012

Parasomnias induced by hypnosedatives are rare but serious side effect. Such parasomnias have not been reported with all hypnosedatives. However, frequent use of hypnosedatives, particularly nonbenzodiazepine receptor agonists is associated with parasomnias. Associated symptoms are sleep eating, sleepwalking with object manipulation, sleep conversations, sleep driving, sleep sex and sleep shopping etc. Mechanisms include high affinity for $GABA_A$ receptor, interruption of the consolidation phase of memory formation by drug, pharmacokinetic or pharmacodynamic drug-drug interaction and concomitant administration with alcohol. Managements for parasomnias induced by hypnosedatives involve stopping medication, switch to other medications or nonpharmacological treatment, lowest effective dose of NBRAs (Non-Benzodiazepine Receptor Agonists), taking into consideration drug-drug interactions, identification and treatment of underlying disease states.

• Mass Spectrometry Letters
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• 제4권2호
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• pp.34-37
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• 2013

Honokiol and magnolol, the major bioactive neolignans of magnolia officinalis, are the most important constituents of the crude drug prescriptions that are used in the therapy of neuroses and various nervous disorders. There have been limited reports on the effects of neolignoid compounds on human cytochrome P450 activity. Therefore, the inhibitory effects of honokiol and magnolol on seven human cytochrome P450 s were evaluated in human liver microsomes. Honokiol and magnolol showed the most potent inhibition of CYP1A2-mediated phenacetin O-deethylase activity ($IC_{50}$ values of 3.5 and 5.4 mM, respectively) among the seven P450s tested. These in vitro data indicate that neolignan compounds can inhibit the activity of CYP1A2 and suggest that these compounds should be examined for potential pharmacokinetic drug interactions in vivo.

• Biomolecules & Therapeutics
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• 제4권3호
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• pp.209-223
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• 1996

Chirality is important in the context of biological activity because at a molecular level, asymmetry dominates biological process. While most pharmaceuticals of natural origin are single enantiomers, most of the synthesized chiral drugs are used in the form of racemic mixtures of two or more diastereomers. The enantiomers of a racemic drug generally differ in pharmacodynamic and pharmacokinetic properties as a consequence of stereoselective interaction with optically active molecular components of living organism. In pharmacokinetics and pharmacodynamics enantioselectivity plays an important role. The information on the sum of eutomer and distorter in a racemic drugs is very important in the estimation of therapeutic advantage and/or toxicity of racemates. The choice of preferentially developing a single enantiomer should be based on actual therapeutic advantages and especially improved safety.

• Journal of Pharmaceutical Investigation
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• 제33권3호
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• pp.171-178
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• 2003

Drug interactions with food, on occasion, lead to serious nutritional and functional changes in the body as well as alterations of pharmacological effect. It, therefore, should be necessary to take drug interactions with food into consideration for effective and safe therapeutics. Diabetes mellitus is a heterogeneous group of disorders characterzed by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with increased risk of microvascular, macrovascular, and neuropathic complications. However, the precise mechanism of diabetes mellitus remains unclear. Three basic objectives in the care of diabetic patients are maintaining optimal nutrition, avoiding hypo- or hyperglycemia and preventing complications. Laminaria japonica is a brown macroalgae which can be used as a functional diet due to high content of diatery fiber. The purpose of this study was to investigate the effect of Laminaria japonica diet on the pharmacokinetics of metformin which are frequently used in the treatment of diabetes. Diabetic rats induced by streptozotocin were employed in this study. Blood concentrations of oral hypoglycemic agent, metformin, were measured by HPLC and resultant pharmacokinetic parameters were calculated by RSTRIP. The mechanisms of drug interaction with food were evaluated on the basis of pharmacokinetic parameters such as $k_{a},\;t_{1/2},\;C_{max},\;t_{max}$, and AUC. Administration of metformin in normal and diabetic rats treated with Laminaria japonica diet showed significant decrease in AUC, $C_{max},\;and\;k_a$, and increase in $t_{max}$, compared to those with normal diet. This might result from adsortion of metformin on components of Laminaria japonica, causing delayed absorption. The oral glucose test showed that Laminaria japonica diet could lower blood glucose level probably through either inhibiting the activity of disaccharidases, intestinal digestive enzymes, or delaying the absorption of glucose. More studies should be followed to fully understand pharmacokinetic changes of metformin caused by long-term Laminaria japonica diet.

• Journal of Pharmaceutical Investigation
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• 제33권2호
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• pp.113-120
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• 2003

Drug interactions with food, on occasion, lead to serious nutritional and functional changes in the body as well as alternations of pharmacological effect. It, therefore, should be necessary to take drug interactions with food into consideration for effective and safe therapeutics. Diabetes mellitus is a heterogeneous group of disorders characterized by abnormal glucose homeostasis, resulting in hyperglycemia, and is associated with increased risk of micovascular, macrovascular, and neuropathic complications. However, the precise mechanism of diabetes mellitus remains unclear. Three basic objectives in the care of diabetic patients are maintaining optimal nutrition, avoiding hypo- or hyperglycemia and preventing complications. The purpose of this study was to investigate thε effect of Laminaria japonica diet on the absorption, distribution, metabolism and excretion of glipizide which are frequently used in the treatment of diabetes. Diabetic rats induced by streptozotocin were employed in this study. Blood concentrations of oral hypoglycemic agents were measured by HPLC and resultant pharmacokinetic parameters were calculated by RSTRIP. The mechanisms of drug interaction with food were evaluated on the basis of pharmacokinetic parameters such as $k_{a},\;t_{1/2},\;C_{max},\;t_{max}$ and AUC. Administration of glipizide in normal rats treated with Laminaria japonica diet showed significant increase in AUC, $k_{a},\;t_{1/2},\;t_{max}$ and decrease in $C_{max}$, compared to those without Laminaria japonica diet. This might result from adsorption of glipizide on components of Laminaria japonica, causing delayed absorption. Administration of glipizide in diabetic rats treated with Laminaria japonica diet showed significant increase in $t_{1/2}\;and\;t_{max}$, and decrease in $C_{max}$, compared to those without Laminaria japonica diet. This might also result from adsorption of glipizide on components of Laminaria japonica, causing delayed absorption and flattened blood concentration of glipizide. The oral glucose test showed that Laminaria japonica diet could lower blood glucose level probably through either inhibiting the activity of disaccharidases, intestinal digestive enzymes, or delaying the absorption of glucose. More studies should be followed to fully understand pharmacokinetic changes of glipizide caused by long-term Laminaria japonica diet.

• The Korean Journal of Physiology and Pharmacology
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• 제21권1호
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• pp.107-115
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• 2017

Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the "fit for purpose" application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in $C_{max}$ of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.

• 한국임상약학회지
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• 제26권4호
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• pp.312-317
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• 2016

Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.

• 생물정신의학
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• 제7권1호
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• pp.14-20
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• 2000

Recently atypical antipsychotics have been used as first line agent in the treatment of schizophrenia, and also played a significant role in the treatment of many kinds of psychiatric disorders. The pharmacokinetic and pharmacodynamic properties of these newer antipsychotics are well known through preclinical and early clinical trials. However, it is important to note the limitations of the results due to its relatively short experience. Clozapine is eliminated principally by the hepatic P450 1A2 and 3A4 cytochrome enzymes. 1A2 inducers such as carbamazepine and smoking can reduce its half-life, while 1A2 inhibitors such as SSRIs, especially fluvoxamine can increase its duration of action. Carbamazepine should be avoided in a patient on clozapine because of carbamazepine's potential effects on bone marrow. Benzodiazepines tend to increase the chances of sedation, delirium and respiratory depression. Risperidone is metabolized to 9-hydroxyriperidone by the hepatic P450 2D6 cytochrome enzymes. Fluoxetine and paroxetine, 2D6 inhibitors interfere with metabolism, but 9-hydroxyrisperidone has similar biological activity as parental drug, so it has little affect on the outcome. Olanzapine shows minimal capacity to inhibit cytochrome P450 isoenzymes and shows minimal chance of drug interaction. It is eliminated principally by the hepatic P450 1A2 and 2D6 cytochrome enzymes.