• Biomolecules & Therapeutics
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• 제23권3호
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• pp.296-300
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• 2015

${\beta}$-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of ${\beta}$-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of ${\beta}$-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of ${\beta}$-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of ${\beta}$-lapachone was 15.5%. The considerable degradation of ${\beta}$-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of ${\beta}$-lapachone may be resulted from the first-pass metabolic degradation of ${\beta}$-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.

• Journal of Pharmaceutical Investigation
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• 제41권5호
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• pp.301-307
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• 2011

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $17.1{\mu}M$. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve ($AUC_{0-\infty}$) and the peak plasma concentration ($C_{max}$) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was significantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimodipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol.

• Biomolecules & Therapeutics
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• 제18권1호
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• pp.106-110
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• 2010

The pharmacokinetics and bioavailability of ambroxol, an expectoration improver and mucolytic agent, were studied to determine the feasibility of enhanced transdermal delivery of ambroxol from the ethylene-vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether as an enhancer in rats. The ambroxol-010 matrix system (15 mg/kg) was applied to abdominal skin of rats. Blood samples were collected via the femoral artery for 28 hrs and the plasma concentrations of ambroxol were determined by HPLC. Pharmacokinetic parameters were calculated using Lagran method computer program. The area under the curve (AUC) was significantly higher in the enhancer group ($1,678{\pm}1,413.3\;ng/ml{\cdot}hr$) than that in the control group $1,112{\pm}279\;ng/ml{\cdot}hr$), that is treated transdermally without enhancer, showing about 151% increased bioavailability (p<0.05). The average $C_{max}$ was increased in the enhancer group ($86.0{\pm}21.5\;ng$/ml) compared with the control group ($59.0{\pm}14.8\;ng$/ml). The absolute bioavailability was 13.9% in the transdermal control group, 21.1% in the transdermal enhancer group and 18.1% in the oral administration group compared with the IV group. The $T_{max}$, $K_a$, MRT and $t_{1/2}$ of ambroxol in transdermal enhancer group were increased significantly (p<0.01) compared to those of oral administration. As the ambroxol-EVA matrix containing polyoxyethylene-2-oleyl ether and tributyl citrate was administered to rats via the transdermal routes, the relative bioavailability increased about 1.51-fold compared to the control group, showing a relatively constant, sustained blood concentration. The results of this study show that ambroxol-EVA matrix could be developed as a transdermal delivery system providing sustained plasma concentration.

• 약학회지
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• 제49권3호
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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.

• Archives of Pharmacal Research
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• 제28권4호
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• pp.469-475
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• 2005

The purpose of this study was to investigate the effect of a cotreatment of bamboo concentrates (Jukcho solution; 0.75, 1.5, and 3.0 mL/kg) with the chemotherapeutic agent paclitaxel on the bioavailability of orally administered paclitaxel (50 mg/kg) in rats. The effect of a pretreatment of bamboo concentrates (1.5 and 3.0 mL/kg for 1.0 h or a consecutive 3 day) was also examined. The paclitaxel plasma concentrations of rats orally administered paclitaxel plus bamboo concentrates (coadministration, 3.0 mL/kg and pretreatment, 1.5 and 3.0 mL/kg) were significantly higher than those of rats treated with paclitaxel alone. Plasma concentrations of paclitaxel in groups pretreated with bamboo concentrates for 3 day were markedly higher than those of a paclitaxel control group at the measured time points. The areas under plasma concentration-time curves (AUCs) of paclitaxel in groups pretreated with bamboo concentrates were elevated and the absolute bioavailability ($AB\%$) and relative bioavailability ($RB\%$) of paclitaxel were also significantly higher than those in the control group. The peak concentration ($C_{max}$), half-life ($t_{1/2}$), and the elimination rate constant ($K_{el}$) of paclitaxel after 3 day of pretreatment with bamboo concentrates were also significantly higher than those in the control, but the time required to reach the maximum plasma concentration ($T_{max}$) of paclitaxel was unaffected by the bamooo concentrates. Western blot analyses demonstrated that the level of CYP3A4 was increased in the livers of rats treated orally with paclitaxel, but this was reversed by pretreating with bamboo concentrates. These results show that bamboo concentrates enhance the bioavailability of orally administered paclitaxel and this effect may be associated with a diminished expression of CYP3A4 in the liver.

• Biomolecules & Therapeutics
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• 제19권3호
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• pp.364-370
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• 2011

The purpose of this study was to investigate the effects of curcumin on the pharmacokinetics of loratadine in rats. The effect of curcumin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Pharmacokinetic parameters of loratadine were also determined after oral and intravenous administration in the presence or absence of curcumin. Curcumin inhibited CYP3A4 activity with an IC50 value of 2.71 ${\mu}M$ and the relative cellular uptake of rhodamine-123 was comparable. Compared to the oral control group, curcumin significantly increased the area under the plasma concentration-time curve and the peak plasma concentration by 39.4-66.7% and 34.2-61.5%. Curcumin also significantly increased the absolute bioavailability of loratadine by 40.0-66.1% compared to the oral control group. Consequently, the relative bioavailability of loratadine was increased by 1.39- to 1.67-fold. In contrast, curcumin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that the enhanced oral bioavailability may be mainly due to increased intestinal absorption caused via P-gp and CYP3A4 inhibition by curcumin rather than to reduced renal and hepatic elimination of loratadine. Curcumin enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced fi rst-pass metabolism of loratadine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by curcumin.

• 약학회지
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• 제53권5호
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• pp.259-264
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• 2009

The present study was to investigate the effect of naringin, a flavonoid, on the pharmacokinetics of losartan in rats. Pharmacokinetic parameters of losartan in rats were determined after an oral administration of losartan (9 mg/kg) in the presence or absence of naringin (0.5, 2.5 and 10 mg/kg). The pharmacokinetic parameters of losartan were significantly altered by the presence of naringin compared with the control group (given losartan alone). Presence of naringin significantly (p<0.05, 2.5 mg/kg; p<0.01, 10 mg/kg) increased the area under the plasma concentration?time curve (AUC) of losartan by 43.7~63.0% and peak plasma concentration ($C_{max}$) of losartan by 31.7~45.5%. Consequently, the absolute bioavailability (AB) of losartan in the presence of naringin was 43.8~62.9%, which was enhanced significantly (p<0.05, p<0.01) compared to that in the oral control group (22.4%). The relative bioavailability (R.B.) of losartan increased by 1.44- to 1.63-fold in the presence of naringin. However, there was no significant change in the peak plasma concentration ($T_{max}$) and terminal half-life ($t_{1/2}$) of losartan in the presence of naringin. In conclusion, the presence of naringin significantly enhanced the oral bioavailability of losartan, implying that presence of naringin might be mainly effective to inhibit the cytochrome P450 (CYP)3A-mediated metabolism, resulting in reducing gastrointestinal and hepatic first-pass metabilism and Pglycoprotein (P-gp)-mediated efflux of losartan in small intestine. Concurrent use of naringin or naringin-containing dietary supplement with losartan should require close monitoring for potential drug interactions.

• Journal of Pharmaceutical Investigation
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• 제36권3호
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• pp.157-160
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• 2006

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<0.05 at 5 mg/kg; p<0.01 at 10 mg/kg) increased the area under the plasma concentration-time curve (AUC), peak plasma concentrations $(C_{max})$ 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<0.05 at 5 mg/kg; p<0.01 at 10 mg/kg), and the relative bioavailability (RB%) of ambroxol with clarithromycin was increased by 1.32-to 1.71-fold. However, there were no significant changes in time to reach peak concentration $(T_{max})$ 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.

• 약학회지
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• 제48권4호
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• pp.226-230
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• 2004

The pharmacokinetics of orally administered paclitlxel (50 mg/kg) was studied in six rabbits after 1hr pretreatment (2.0 mg/kg and 10 mg/kg) of tetramethoxyflavone or coadministration of (2.0 mg/kg, 10 mg/kg and 20 mg/kg) tetramethoxyflavone. The area under the plasma concentration-tine curve (AUC) and plasma concentration of paclitaxe1 coadministered with tetramethoxyflavone (10 mglkg) were increased significantly (p<0.05) compared with control. However, coadministration of tetramethoxyflavone (2 and 20 mg/kg) showed no significant effect on the pharmacokinetic parameters of paclitaxel. Pretreatment with tetramethoxyflavone significantly (p<0.05) increased the plasma concentration of paclitaxel. The area under the plasma concentration-time curve (AUC) and the peak concentration (C$_{max}$) of paclitaxel pretreated with tetramethoxyflavone were increased significantly (p<0.01, p<0.05) compared with control. The terminal half. life of paclitaxel pretreated with tetramethoxyflavone (2 mg/kg and 10 mg/kg) was significantly (p<0.05) prolonged compared with control. Pretreatment with tetramethoxyflavone (2.0 mg/kg, 10 mg/kg) significantly (p<0.01, p<0.05) increased the absolute bioavailability of paclitaxel compared with the control (154∼179%). On the basis of the results, it might be considered that tetramethoxyflavone may inhibit cytochrome P450 or P-glycoprotein efflux pump which are engaged in paclitaxel metabolism, result in increased AUC and t$_{1}$2/ of paclitaxel. However, further study should be conducted to clarify the roles of cytochrome P450 and P-glycoprotein on paclitaxel bioavailability with/or without tetramethoxyflavone. P-glycoprotein on paclitaxel bioavailability with/or without tetramethoxyflavone.

• 한국임상약학회지
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• 제20권3호
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• pp.200-204
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• 2010

The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of nimodipine in rats. Pharmacokinetic parameters of nimodipine were determined in rats after oral administration of nimodipine (16 mg/kg) with or without ticlopidine (3 or 10 mg/kg). Ticlopidine inhibited cytochrome P450 (CYP)3A4 activity. Ticlopidine significantly (p<0.05, 10 mg/kg) increased the area under the plasma concentration-time curve (AUC) of nimodipine and ticlopidine significantly (p<0.05, 10 mg/kg) prolonged the terminal half-life ($t_{1/2}$) of nimodipine. Ticlopidine significantly (p<0.05, 10 mg/kg) decreased the total body clearance ($CL_t$). The absolute bioavailability (AB%) and relative bioavailability (RB%) of nimodipine by presence of ticlopidine were increased by 14% and by 42%, respectively, compared to the control. Based on these results, the increased bioavailability of nimodipine might be due to inhibition of the metabolizing enzyme cytochrome P450 (CYP)3A4 in the liver or intestinal mucosa and/or reducing total body clearance by ticlopidine.