• Biomolecules & Therapeutics
• /
• 제19권2호
• /
• pp.237-242
• /
• 2011

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 ($IC_{50}$) of 18 ${\mu}M$. Compared with the control group, the area under the plasma concentration-time curve (AUC) was significantly increased by 33.0%, and the peak concentration ($C_{max}$) 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 effl ux in the intestinal or in the liver and renal elimination of carvedilol by glipizide.

• Biomolecules & Therapeutics
• /
• 제18권3호
• /
• pp.343-349
• /
• 2010

This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $25.2\;{\mu}M$. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration ($C_{max}$) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
• /
• pp.421.3-422
• /
• 2002

Carvedilol is a nonselective $\beta$-adrenoblocking agent with vasodilating activities. The pharmacokinetics and pharmacodynamics of carvedilol were studied in healthy volunteers following single oral administration. After oral administration of carvedilol 25mg. blood samples were collected for a period of 30 hours. Plasma concentrations of carvedilol were determined by HPLC with spectrofluorometric detection. The effects of carvedilol on systolic and diastolic blood pressure (BP) and heart rate (HR) were measured during the same period. (omitted)

• Archives of Pharmacal Research
• /
• 제27권9호
• /
• pp.973-977
• /
• 2004

Carvedilol is administered as a racemic mixture of the R(＋)- and S(-)-enantiomers, although they exhibit different pharmacological effects. To investigate the stereoselective pharmacoki-netics, the enantiomeric separation of carvedilol in human plasma was undertaken using capil-lary electrophoresis (CE). Resolution of the enantiomers was achieved using 2-hydoxypropyl-$\beta$-cyclodextrin as the chiral selector. Phosphate buffer (50 mM, pH 4.0) containing 10 mM of 2-hydoxypropropyl-$\beta$-cyclodextrin was used as electrolytic buffer. Achiral separation was carried out with the same electrolytic buffer without chiral selector. Following a single oral administra-tion of 25-mg carvedilol to 11 healthy, male volunteers, stereoselective pharmacokinetic analy-sis was undertaken. The maximum plasma concentrations ( $C_{max}$) were 48.9 and 21.6 ng/mL for (R)-carvedilol and (S)-carvedilol, respectively, determined by the chiral method. The profiles of the plasma concentration of (RS)-carvedilol showed $C_{max}$ of 71.5, 72.2, and 73.5 ng/mL, as determined by the CE, HPLC/FD methods and calculations from the data of the chiral method, respectively.y.y.

• Journal of Pharmaceutical Investigation
• /
• 제41권3호
• /
• pp.153-159
• /
• 2011

This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol after oral 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) 2C9 and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 5.2 ${\mu}M$ and 85.4 ${\mu}M$, respectively. In addition, silibinin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under the plasma concentration-time curve was significantly increased by 36.3-57.1%, and the peak concentration was significantly increased 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 by 38.6-59.7%. 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 of carvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin.

• 생명과학회지
• /
• 제33권3호
• /
• pp.268-276
• /
• 2023

본 연구는 carvedilol과 ivabradine의 이층정 제형 개발에 있어 carvedilol 속방층의 제형조건을 최적화하기 위해 수행되었다. Full-factorial design of experiments를 사용하여 carvedilol 속방층(wet granulation part)의 첨가제(microcrystalline cellulose, citric acid, crospovidone) 및 타정 시 공정변수(main compression)를 확인하였고 각 독립변수에 대한 7가지 종속변수(함량, 함량 균일성, 경도, 마손도, 붕해, 용출(pH 1.2 및 6.8)를 design expert software를 사용하여 평가하였다. Design of experiments (DoE) 실험에서 도출된 Analysis of Variance (ANOVA) 결과를 통해 main compression은 경도, 마손도, 붕해 시간에 유의한 영향을 주었고, microcrystalline cellulose는 마손도, 용출에 주요한 영향을 주었음을 확인하였다. 또한, citric acid는 마손도, crospovidone은 마손도, 용출에 주요한 영향을 주었음을 확인하였다. DoE실험 결과를 종합하여 최종적으로 도출된 설계공간에 따라 microcrystalline cellulose (약 18.0-32.0 mg), citric acid (약 0.5-12.0 mg), main compression (약 615-837 kgf)의 최적의 범위 내에서 초기 위험평가에서 평가된 모든 위험요인이 제거된 carvedilol 속방층의 최적 제조 범위를 확인하였다.

• 분석과학
• /
• 제19권4호
• /
• pp.275-279
• /
• 2006

A capillary electrophoresis method for the separation of carvedilol and its metabolites enantiomers using cyclodextrins as the chiral selectors was developed. The effect of several types of cyclodextrins, concentration and capillary temperature for enantiomer resolution were investigated. Best results were obtained by 15 mM carboxymethyl-${\beta}$-cyclodextrin in the run buffer. Also the effect of capillary temperature on efficiency was assessed. The optimized method was applied for separation of chiral carvedilol and its three metabolites.

• 약학회지
• /
• 제45권6호
• /
• pp.650-655
• /
• 2001

Carvedilol is a nonselective $\beta$-blocking agent with vasodilating properties that are attributed mainly to its blocking activity at $\alpha$$^{1}$-receptors. Carvedilol is used in the treatment of mild to moderate hypertention and angina pectoris and is often used in combination with other drugs. This study was carried out to evaluate the bioequivalence and pharmacokinetics of two carvedilol 25mg tablet formulations according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty healthy volunteers are enrolled and received a single dose (25mg as carvedilol) of each drug in the fasting state, in a randomized 2-way crossover design. After oral administration, blond samples were collected for a period of 30 hours. Plasma concentrations of carvedilol were determined by a rapid and sensitive HPLC method with spectrofluorometric detection. The major pharmacokinetic parameters such as AU $C_{0-}$30hr/, AU $C_{inf}$ , $C_{max}$, $T_{max}$, $t_{1}$2 / Cl/F and V $_{\beta}$//F were calculated. ANOVA test and t-test were utilized for the statistical analysis of each parameter. The results showed that the differences in AU $C_{0-}$30hr/, $C_{max}$ and $T_{max}$ between two were ~5.66, 1.74 and 0.00%, respectively. Minimum detectable differences ($\Delta$) at $\alpha$=0.05 were less than$\pm$ 20% except $T_{max}$ (8.44, 18.36, and 33.86%, respectively). The 90% confidence intervals of all parameters were within $\pm$20% (-10.60~ -0.72, -9.00~12.49 and -19.81~19.81%, respectively). Therefore, it is concluded that the two formulations are bioequivalent for both the extent and the rate of absorption after single dose administration.ation.ion.ion.ation.ion.n.

• Journal of Pharmaceutical Investigation
• /
• 제41권6호
• /
• pp.363-369
• /
• 2011

In this study, we demonstrated the release behavior of carvedilol with the content of polyvinylpyrrolidone K-30 (PVP K-30) and the effect of citric acid and fumaric acid as acidifiers on the release behavior of drug. In addition, it tries to inquire into the release behavior difference of the carvedilol according to the manufacturing method. The release behavior of the tablets was compared with Dilatrand$^{(R)}$ in the simulated gastric fluid (pH1.2). Differential scanning calorimeter (DSC), X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR) were characterized for the physicochemical properties of the tablets. In case of mixing the carvedilol and PVP K-30, in case the ratio of the carvedilol and PVP K-30 was 1:5, the release behavior was the highest among. As well as the dissolution rate of tablets manufactured by lyophilization and rotary evaporator was higher than physical mixture. The dissolution rate of containing acidifiers was more improved. But, rather the excessive amount of the acidifier addition reduced the dissolution rate.

• Journal of Pharmaceutical Investigation
• /
• 제41권3호
• /
• pp.179-184
• /
• 2011

This study aimed to confirm the effect of molecular weight (MW) in solid dispersion of carvedilol with poly-vinylpyrrolidone (PVP) of various MW. Solid dispersion of carvedilol with PVP was prepared by spray-drying method. Scanning electron microscopy (SEM) was used to analyze the surface of solid dispersion samples. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to analyze the crystalline of solid dispersion. Fourier transform infrared spectroscopy (FT-IR) was used to analyze the change of chemical structure characteristic of solid dispersion. DSC and XRD show that drug crystalline was changed. FT-IR revealed that chemical structure of solid dispersion comparing the chemical structure of drug was changed. The dissolution studies of solid dispersion presented at simulated gastric juice (pH 1.2). The dissolution rate of solid dispersion was dramatically enhanced than pure drug and the MW of PVP has an effect on the release property of carvedilol in solid dispersion. In conclusion, the present study has confirmed the effect of MW of PVP on release property of solid dispersion formulation of carvedilol with PVP.