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The purpose of this study was to investigate the effects of cilostazol on the bioavailability and pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined following oral and intravenous administration of nifedipine (1.5 and 6.0 mg ・ kg-1) in rats. Cilostazol inhibited CYP3A4 enzyme activity at a 50% inhibitory concentration (IC50) of 4.1 μM. The areas under the plasma concentration–time curve (AUC 0-∞) and the peak concentration (C max) of nifedipine were significantly increased, respectively, in the presence of cilostazol compared to that in the control. The total body clearance (CL/F) was significantly decreased by cilostazol. Consequently, the absolute bioavailability (AB) of nifedipine with cilostazol was significantly higher than that in the control. The metabolite to parent AUC ratio (MR) in the presence of cilostazol was significantly decreased compared to that in the control. The AUC 0-∞ of intravenous nifedipine was significantly increased with cilostazol compared to that in the control. The increased bioavailability of nifedipine in rats can be mainly due to the inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver by cilostazol. In addition, the reduction of CL/F of nifedipine by cilostazol may also be a factor.

− This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol afteroral administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) with oral silibinin (0.3, 1.5 or 6 mg/kg) and intravenously (1 mg/kg) to rats. The effects of silibinin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibitionconcentration (IC 50 ) of 5.2 µ M and 85.4 µ M, respectively. In addition, silibinin significantly enhanced the cellular accu-mulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under theplasma concentration–time curve was significantly increased by 36.3–57.1%, and the peak concentration was significantlyincreased by 51.1–88.5% in the presence of silibinin after oral administration of carvedilol. Consequently, the relative bio-availability of carvedilol was increased by 1.13- to 1.57-fold and the absolute bioavailability was significantly increased by38.6–59.7%. The time to reach peak concentration and the terminal half-life were not significant. The enhanced oral bio-availability of carvedilol may result from inhibition of CYP2C9-mediated metabolism and P-gp-mediated efflux ofcarvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin. Key words

This study was designed to investigate the effects of glipizide on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Clinically carvedilol and glipizide can be prescribed for treatment of cardiovascular diseases as the complications of diabetes, and then, Carvedilol and glipizide are all substrates of CYP2C9 enzymes. Carvedilol was administered orally or intravenously without or with oral administration of glipizide to rats. The effects of glipizide on cytochrome P450 (CYP) 2C9 activity and P-gp activity were also evaluated. Glipizide inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 18 μM. Compared with the control group, the area under the plasma concentration-time curve (AUC) was significantly increased by 33.0%, and the peak concentration (Cmax) was significantly increased by 50.0% in the presence of glipizide after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.13- to 1.33-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of glipizide was increased by 36.8%. After intravenous administration, compared to the control, glipizide could not significantly change the pharmacokinetic parameters of carvedilol. Therefore, the enhanced oral bioavailability of carvedilol may mainly result from inhibition of CYP2C9- mediated metabolism rather than both P-gp-mediated efflux in the intestinal or in the liver and renal elimination of carvedilol by glipizide.

This study aimed to investigate the effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats. Intravenous (6 mg/kg) or oral (2 mg/kg) etoposide was administered to rats in the absence and the presence of oral curcumin (0.4, 2 or 8 mg/kg). The effects of curcumin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Curcumin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration (IC(50) ) of 2.7 µM. In addition, curcumin (10 µm) significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given etoposide alone), curcumin (2 or 8 mg/kg) increased significantly the oral bioavailability (AUC and C(max) ) of etoposide. Consequently, the extent of absolute oral bioavailability (F) of etoposide with curcumin was significantly enhanced compared with that in the control group. In contrast, curcumin did not affect the pharmacokinetics of etoposide after intravenous administration. Therefore, the enhanced oral bioavailability of etoposide in the presence of curcumin might be due mainly to inhibition of the P-gp efflux pump in the small intestine and possibly by reduced first-pass metabolism of etoposide in the small intestine by inhibition of CYP3A activity in rats. The combined use of curcumin may be helpful to improve the F of etoposide in chemotherapeutic applications.

【This study investigated the effect of clarithromycin on the pharmacokinetics of ambroxol in rats. The pharmacokinetic parameters of ambroxol in rats were determined after the oral administration of ambroxol (12 mg/kg) in the presence or absence of clarithromycin (5 or 10 mg/kg). Compared with the control (given ambroxol alone), coadministration of clarithromycin significantly (p $(C_{max})$ and absorption rate constant $(K_a)$ of ambroxol. Clarithromycin increased the AUC of ambroxol in a dose dependent manner within the dose range of 5 to 10 mg/kg. The absolute bioavailability (AB%) of ambroxol in the presence of clarithromycin was significantly higher than that of the control (p $(T_{max})$ and terminal half-life $(T_{1/2})$ of ambroxol in the presence of clarithromycin. Coadministration of clarithromycin enhanced the bioavailability of ambroxol, which may be due to the inhibition of intestinal and hepatic metabolism of ambroxol by CYP 3A4. Further studies for the potential drug interaction are necessary since ambroxol is often administrated concomitantly with clarithromycin in humans.】

This study was performed to obtain the good processing in the Relunanniae Radix Preparata. The contents of the Relunanniae Radix and the Relunanniae Radix Preparata produced through different processes were analyzed in the 5-hydroxymethyl-2-furaldehyde (5-HMF), sugar, total nitrogen, crude lipid and ash. 5-HMF was not detected in the Relunanniae Radix, but detected in the Relunanniae Radix Preparata. 5-HMF content was increased gradually with processing times (1∼9 times) and increased expressly in the Relunanniae Radix Preparata steamed for 7 times. Sucrose, fructose and glucose were contained in the Relunanniae Radix, but sucrose was not detected and fructose and glucose were increased largely in the Relunanniae Radix Preparata steamed for 1 time. Fructose and glucose were decreased gradually with processing times (2∼9 times), but the gap of decrease was insignificant. Total nitrogen was changed slightly and crude lipid was decreased slowly with processing times. The ash was suitable to KPⅧ rules (less than 6.0%). From this analysis we found out the content of 5-HMF from Relunanniae Radix Preparata steamed more than 7 times was suitable to KPⅧ rules (more than 0.1%).

This study attempted to prepare polyethylene-glycol modified (PEGylated) and folate-PEGylated liposomes containing paclitaxel (Ptx) in order to reduce the toxicity and improve the bioavailability and biocompatibility by targeting drugs to the lymphatics using cancer cell specific ligand folate to prevent metastasis via the lymphatic system. Liposomes were prepared by lipid film hydration method using PEG and folate-PEG as surface modifiers. The mean particle size and encapsulation efficiency of liposomes were114±6.81 nm and81±2.3% for PEGylated liposome and122±4.87 nm and88±2.0% for folate-PEGylated liposome, respectively. According to stability test, it could be confirmed that PEGylated and folate-PEGylated liposomes were stable for at least 5 days. After intravenous administration of the PEGylated and folate-PEGylated liposomes to rats, theCLt(total clearance) andt1/2(half-life) were significantly different (P<0.05) compared with those of PADEXOL Inj. In targeting efficiency, calculated as the concentration ratio of Ptx in lymph nodes and plasma, there was significant increase in targeting efficiency at lymph nodes (P<0.05). From these results, we could conclude that the prepared Ptx-containing PEGylated and folate-PEGylated liposomes are good candidates for the targeted delivery of the drug to lymphatic system.

Background This study aimed to investigate the effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats. Methods We determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors. We evaluated the effect of HMG-CoA reductase inhibitors on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. Results Atorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities; inhibitory concentration (IC 50 ) values were 47.0, 5.2, 15.0 and 3.3 μM, respectively. Simvastatin and fluvastatin increased the cellular uptake of rhodamine-123. The area under the plasma concentration–time curve (AUC 0–∞ ) and the peak plasma concentration ( C max ) of oral nifedipine were significantly increased by fluvastatin and simvastatin, respectively, compared to control group. The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. The metabolite–parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin were significantly decreased, which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine, respectively. The AUC 0–∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group. Conclusion The increased bioavailability of nifedipine may be mainly due to inhibition of both P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the CL/F of nifedipine by fluvastatin and simvastatin.

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC50) of 4.1 µM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC0-∞ of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.

A detailed study on the structure, dynamics, and thermodynamic behavior of phosphatidylcholine/cholesterol (PC/CHOL) mixtures was undertaken using differential scanning calorimetry (DSC) and solid-state nuclear magnetic resonance (NMR) spectroscopy. DSC thermograms of mixtures of cholesterol (CHOL) with 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC), 1,2-distearoyl-sn-phosphatidylcholine (DSPC), and 1,2-diarachidoyl-sn-phosphatidylcholine (DAPC) showed a broadening of the first-order gel-->liquid crystalline transition and a decrease in the transition enthalpy, indicating a gradual loss of cooperativity for high CHOL concentrations. DPPC and DSPC were labeled with 13C at the carbonyl group of the sn-2 chain and 2H was introduced into the middle of the sn-2 chain at the 6- and 12-position for DPPC and DSPC, respectively. The 13C and 2H NMR spectra of each labeled lipid were studied as a function of temperature and CHOL concentration. The residual quadrupole splitting in the 2H NMR spectra, delta nu Q perpendicular, was analyzed as a function of temperature and composition. For CHOL concentrations less than 30 mol %, a precipitous change in delta nu Q perpendicular occurs near the chain melting temperature of the phospholipid. Further increases in CHOL concentration broaden the transition and shift the midpoint to higher temperature, indicating the presence of a new phase at higher CHOL contents. Moreover, at a given temperature, delta nu Q perpendicular increases with increasing cholesterol content, which indicates a more ordered structure. The 13C NMR spectra in the gel state consisted of a superposition of two components which can be attributed to both gel-like and fluid phospholipid domains in the bilayer. This two-component spectrum can be simulated quantitatively with a two-parameter chemical exchange model, which permits the fraction of each form and the exchange rate to be determined as a function of temperature and composition. At high CHOL contents the line width of the fluid component broadens, suggesting an increase in the exchange rate between the domains. These results were interpreted in terms of a temperature composition diagram with one region L beta', two regions LGI and LGII, and one liquid crystalline region L alpha, with LG denoting "liquid-gel" type phases. Liquid-gel phases correspond to phases with increased order in the hydrocarbon chains (in comparison to that of the pure PC bilayer in the L alpha phase) combined with fast limit axial diffusion that averages the 13C NMR spectrum to a "fluidlike" line.(ABSTRACT TRUNCATED AT 400 WORDS)

Superlattice structures consisting of La0.7MnO3−δ (LMO) and Pr0.65Ba0.05Ca0.3MnO3−δ (PBCMO) systems, in which the thickness of La0.7MnO3−δ is fixed and that of Pr0.65Ba0.05Ca0.3MnO3−δ varied from 1 to 8 unit cells, have been grown in situ on (100) LaAlO3 substrates using a pulsed-laser deposition technique. Microstructural characterization carried out on these films shows the presence of characteristic intense satellite peaks, indicating the chemical modulation of the superlattice structure. The insulator-to-metal transition and the magnetoresistance (MR) ratio are found to vary with the number of unit cells. The samples with 1, 2, 5, and 8 unit cells of Pr0.65Ba0.05Ca0.3MnO3−δ show transition temperatures of 240, 230, 150, and 160 K and MR ratios of 540%, 592%, 3150%, and 2875%, respectively. We have observed an enhancement of magnetoresistance ratios in the case of superlattices with a thickness of PBCMO greater than 5 unit cells, which may be attributed to a ferromagnetic biasing provided by the LMO la...

Silibinin, a flavonoid, is an inhibitor of P-glycoprotein (P-gp)-mediated efflux transporters, and its oxidative metabolism is catalyzed by CYP3A4. The purpose of this study was to investigate the effect of oral silibinin on the bioavailability and pharmacokinetics of orally and intravenously administered paclitaxel in rats. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (4 mg/kg) administration in the presence and absence of silibinin (0.5, 2.5 or 10 mg/kg). The effect of silibinin on the P-gp as well as CYP3A4 activity was also evaluated. Silibinin inhibited CYP3A4 enzyme activity with an IC50 of 1.8 µmol/l. In addition, silibinin significantly inhibited P-gp activity. Compared to the control group, silibinin significantly (p < 0.05 by 2.5 mg/kg, p < 0.01 by 10 mg/kg) increased the area under the plasma concentration-time curve (65.8–101.7% higher) of oral paclitaxel. Silibinin also significantly increased (p < 0.05 by 2.5 mg/kg, 31.0% higher; p < 0.01 by 10 mg/kg, 52.9% higher) the peak plasma concentration of paclitaxel. Consequently, the absolute bioavailability of paclitaxel was increased by silibinin compared to that in the control group, and the relative bioavailability of oral paclitaxel was increased 1.15- to 2.02-fold. The intravenous pharmacokinetics of paclitaxel were not affected by the concurrent use of silibinin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability in the presence of silibinin could mainly be due to the increased intestinal absorption of paclitaxel via P-gp inhibition.

In an effort to achieve high magnetoresistance ratios at high temperature and low fields, we have fabricated superlattice structures consisting of La0.7MnO3−δ (LMO) and Pr0.65Ba0.05Ca0.3MnO3−δ (PBCMO) systems where La0.7MnO3−δ is believed to act as a ferromagnetic biasing source to Pr0.65Ba0.05Ca0.3MnO3−Δ. LMO and PBCMO individually transform to ferromagnetic states at 240 K and 60 K respectively. A series of samples, in which the thickness of La0.7MnO3−δ is fixed and that of Pr0.65Ba0.05Ca0.3MnO3−δ varied from 1 to 8 unit cells, have been grown in situ on (100) LaAlO3 substrates using a pulsed laser deposition technique. Microstructural characterization carried out on these films show the presence of characteristic intense satellite peaks indicating the chemical modulation of the superlattice structure. The insulator-to-metal transition and the MR ratio, defined as [R(0)-R(H)/R(H)], where R(0) and R(H) are resistances in zero and applied fields, is found to vary with the number of unit cells. The samples with 1, 2, 5 and 8 unit cells of Pr0.65Ba0.05Ca0.3MnO3−δ show a transition temperature of 240 K, 230 K, 150 K and 160 K and MR ratio of 540%, 592%, 3150% and 2875 % respectively. We have observed an enhancement of magnetoresistance ratio in case of superlattices with thickness of PBCMO greater than 5 unit cells. We attribute this enhancement to a ferromagnetic biasing provided by the LMO layers acting as a ferromagnetic film below its transition temperature.

Objective: The aim of this study was to investigate the effects of pravastatin on the pharmacokinetics of nimodipine in rats. Materials and Methods: The effect of pravastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Nimodipine was administered to rats intravenously (3 mg/kg) and orally (12 mg/kg) with pravastatin (0.3 and 1 mg/kg). Results: Pravastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC 50 ) of 14 ΅M. Compared with the oral control group, the area under the plasma concentration-time curve (AUC 0-∞ ) of nimodipine was increased significantly. Consequently, the absolute bioavailability (AB) of nimodipine with pravastatin (1 mg/kg) was 31.1%, which was significantly enhanced compared with the oral control group. Moreover, the relative bioavailability (RB) of nimodipine was 1.12- to 1.31-fold greater than that of the control group. Conclusions: The enhanced oral bioavailability of nimodipine might be mainly due to inhibition of the CYP3A-mediated metabolism of nimodipine in the small intestine and/or in the liver and due to reduction of the total body clearance rather than both to inhibition of the P-gp efflux transporter in the small intestine and reduction of renal elimination of nimodipine by pravastatin. The increase in the oral bioavailability of nimodipine with pravastatin should be taken into consideration of potential drug interactions between nimodipine and pravastatin.

Clinical observations were made on 349 cases of acute drug intoxication who were visited to emergency room of Yeungnam University Hospital during recent 7 years from January 1984 to December 1990. The following results were obtained 1) Total number of cases of acute drug intoxication was 349 which was 0.39% of the total patients of the emergency room during the same period. 2) The ratio of male to female was 1.1 : 1. The age incidence was highest in the third decade(26.7%). The monthly incidence was hightest in May. Higher frequency was observed in summer season. 3) The most common drug of the intoxication was pesticides and herbicides(71.9%), the remainders were miscellaneous drugs(11.2%), sedatives(7.7%), rodenticides(6.3%) and unknown drug(3.2%) in orders. 4) The most common cause of drug intoxication was suicide(69.1%) and the others were accident, unknown cause, intention in orders. 5) Main clinical manifestations were the impairment of consciousness, nausea, vomiting and convulsion. Physical examination revealed increased pulses, increased blood pressure, miosis of the pupil and sweating. Above symptoms and signs were more prominent in pesticide intoxication. Leukocytosis, glycosuria and abnormal LFT were common findings in acute intoxications. 6) The complications were developed in 18.3% among 349 cases and the most common complication was respiratory failure, pneumonia, cardiovascular collapse and pulmonary edema in orders. 7) Overall mortality rate was 8.3% of total cases and mortality rate was highest in herbicide intoxication(22.2%).