• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.237-242
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• 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
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• v.16 no.3
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• pp.210-214
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• 2008

The pharmacokinetic parameters and bioavailability of pranoprofen from the gel were measured to determine the enhancing effect of octanoic acid on the transdermal absorption of pranoprofen in rats. 8 mg/kg of pranoprofen was administered from gel with octanoic acid (the enhancer group) or that without octanoic acid (the control group) via the transdermal route, and the results were compared with those obtained from the intravenously (0.5 mg/kg, IV group) or orally administered group (4 mg/kg, oral group). The AUC of the control, the enhancer, the IV, and the oral groups were $20.2{\pm}5.1$, $50.7{\pm}12.7$, $19.9{\pm}2.5$, and $70.5{\pm}17.6\;ug/ml{\cdot}h$ respectively. The average $C_{max}$ of the control and the enhancer group were $0.93{\pm}0.23$ and $2.82{\pm}0.71\;ug/ml$, respectively, and the mean $T_{max}$ of the control and the enhancer group was 7.00 h. The relative bioavailability of the transdermally administered pranoprofen gel containing octanoic acid was approximately 2.50 times higher than the control group, showing a relatively constant, sustained blood concentration with minimal fluctuation. This suggests that it might be feasible to develop a pranoprofen gel preparation containing an enhancer for the transdermal administration, which is more convenient dosage form than the oral dosage forms.

• YAKHAK HOEJI
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• v.49 no.3
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• pp.230-236
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• 2005

The purpose of this study was to investigate the effect of naringin pretreatment on the bioavailability and phar-macokinetics of diltiazem and one of its metabolites, deacetyldiltiazem, in rabbits. Pharmacokinetic parameters of diltiazem and deacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) pretreated with naringin (1.5, 7.5 and 15 mg/kg). Absorption rate constant ($k_a$) of diltiazem after oral administration of diltiazem pretreated with naringin was significantly (p<0.05 or p<0.0l) increased compared to the control group. Area under the plasma concentration-time curve (AUC) and peak concentration ($C_{max}$) of the diltiazem were significantly (p<0.05 or p<0.01) higher than those of the control. Absolute bioavailability ($AB\%$) of diltiazem pretreated with naringin ranged from $13.5\%$ to $18.6\%$, being enhanced compared to that of the control, $7.2\%$. Relative bioavailability ($RB\%$) of diltiazem was $1.9\~2.6$ times higher than that of the control group. There was no significant change in terminal half-life ($t_{1/2}$) and $T_{max}$ of diltiazem in the presence of naringin. AUC of deacetyldiltiazem pretreated with naringin was significantly (p<0.05) higher than (p<0.05) that of the control. But the metabolite ratios (MR) were significantly decreased (p<0.05), implying that pretreatment of naringin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. In this study, pretreatment of naringin significantly enhanced the oral bioavailability of diltiazem. These results suggested that the diltiazem dosage should be adjusted when it is administered with naringin or a naringin-containing dietary supplement in the clinical setting.

• Journal of Pharmaceutical Investigation
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• v.41 no.2
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• pp.75-82
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• 2011

LB71350 is an HIV protease inhibitor with poor aqueous solubility and extensive first pass effect. The purpose of the present study was to test the feasibility of solid dosage form of LB71350 with improved bioavailability utilizing solid dispersion. Three different compositions with varying ratio of (LB71350: Gelucire 44/14: Tween 20) were studied. Capsule filling of these solid dispersion compositions was tested using a semi-automatic capsule filling system. Oral bioavailability in dog was tested. Chemical and physical stability at 4, 25 and $40^{\circ}C$ was monitored by HPLC assay, dissolution test, powder XRD and microscopy. The capsule filling system yielded uniform products of drug loading up to 10%. Oral bioavailability in dog was improved compared to the aqueous suspension of crystalline LB71350. Capsules were chemically stable for up to 6 months at $40^{\circ}C$. However, there were temperature and composition dependent physical changes. Decrease in dissolution rates after storage at $40^{\circ}C$ was due to the polymorphic change. In conclusion, manufacturing process, bioavailability, and physico-chemical stability have been considered to propose a solid dispersion capsule formulation for the HIV protease inhibitor with poor physico-chemical properties. A new less soluble crystalline form identified during the physical stability test warrants further study.

• YAKHAK HOEJI
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• v.55 no.4
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• pp.332-337
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• 2011

The purpose of this study was to investigate the effect of epigallocatechin gallate (EGCG) on the pharmacokinetics of nimodipine in rats. Pharmacokinetic parameters of nimodipine were determined in rats after oral and iv administration of nimodipine with or without EGCG and also the effect of EGCG on the cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) activity were evaluated. EGCG inhibited CYP3A4 and P-gp activity. EGCG significantly increased the area under the plasma concentration-time curve (AUC) and peak plasma concentration ($C_{max}$) of nimodipine. The absolute bioavailability (AB%) and relative bioavailability (RB%) of nimodipine by EGCG were increased by 16% and by 48%, respectively, compared to the control. In contrast, EGCG did not affect the intravenous pharmacokinetics of nimodipine. Based on these results, the increased bioavailability of nimodipine might be due to inhibition of CYP3A4 in the small intestine and/or in the liver and inhibition of P-gp in the small intestine by EGCG.

• Biomolecules & Therapeutics
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• v.18 no.2
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• pp.226-232
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• 2010

The aim of this study was to investigate the effect of atrovasatatin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine to rats. Nicardipine was administered orally (12 mg/kg) or intravenously (i.v., 4 mg/kg) without or with oral administration of atrovasatatin (0.3 or 1.0 mg/kg) to rats. The effect of atorvastatin on the P-glycoprotein (P-gp) as well as CYP3A4 activity was also evaluated. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 48 ${\mu}M$. Compared to the controls (nicardipine alone), the area under the plasma concentration-time curve (AUC) of nicardipine was significantly (1.0 mg/kg, p<0.05) greater by 16.8-45.4%, and the peak plasma concentration ($C_{max}$) was significantly (1.0 mg/kg, p<0.05) higher by 28.0% after oral administration of nicardipine with atorvastatin, respectively. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.17- to 1.45-fold and the absolute bioavailability (A.B.) of nicardipine with atrovasatatin was significantly greater by 16.7-20.9% compared to that of the controls (14.3%). Compared to the i.v. control, atrovasatatin did not significantly change pharmacokinetic parameters of i.v. administration nicardipine. The enhanced oral bioavailability of nicardipine by atorvastatin suggests that CYP3A subfamily-mediated metabolism were inhibited in the intestine and/or in the liver rather than P-gp-mediated efflux of nicardipine. Based on these results, modification of nicardipine of dosage regimen is required in the patients. Human studies are required to prove the above hypothesis.

• Journal of Pharmaceutical Investigation
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• v.41 no.5
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• pp.273-278
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• 2011

The aim of this study was to investigate the effect of efonidipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

• Biomolecules & Therapeutics
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• v.19 no.4
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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.

• Korean Journal of Clinical Pharmacy
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• v.8 no.2
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• pp.133-138
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• 1998

Phthalimidyl ester of ceftezole (CFZ-PT) was synthesized as a prodrug by esterification of ceftezole (CFZ) with N-bromophthalimide. CFZ-PT was more lipophilic than CFZ when the lipophilicity was assessed by partition coefficients between n-octanol and water at various pH. The pharmacokinetic characteristic of CFZ-PT and CFZ preparations were compared following oral administrations of these compounds to rabbits. CFZ-PT is expected to be metabolized rapidly to CFZ in the body. The metabolism process appears to be hydrolysis of the ester to CFZ, the parent drug of CFZ-PT. In vivo metabolism of CFZ-PT to CFZ was confirmed in rabbit by HPLC analysis. CFZ concentration in the serum samples taken after oral administration of CFZ-PT(equivalent amount of CFZ) were released and higher than those of CFZ. Oral bioavailability of CFZ-PT was 1.9 fold higher than at of CFZ in rabbits because of enhanced lipophilicity and absorption. Finally, it was concluded that CFZ-PT appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.

• Journal of Pharmaceutical Investigation
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• v.27 no.2
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• pp.125-131
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• 1997

Ethoxycarbonyloxyethyl ester of ceftezole (CFZ-ET) was synthesized as a prodrug by esterification of ceftezole (CFZ) with ethoxycarbonyloxyethyl chloride and was confirmed by spectroscopic analyses. CFZ-ET was more lipophillic than CFZ as assessed by n-octanol and water partition coefficients at various pH. CFZ-ET itself did not show any microbiological activity in vitro, but showed substaintial microbiological activity after oral administration of CFZ-ET, indicating that CFZ-ET is converted to microbiologically active metabolite, probably CFZ, in the body. When CFZ-ET was incubated in blood, liver and intestine homogenates of rabbits, liver homogenate showed the fastest conversion of CFZ-ET. CFZ-ET appears rapidly metabolized in the liver when given orally due to the hydrolysis of the ester to CFZ, the parent drug of CFZ-ET. In vivo metabolism of CFZ-ET to CFZ was confirmed in rabbit by HPLC analysis. CFZ-ET were higher than those in the serum samples taken after oral administration of equivalent amount of CFZ. Oral bioavailability of CFZ-ET was 1.5-fold higher than that of CFZ in rabbits because of enhanced lipophilicity and absorption. Based on these findings, CFZ-ET appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.