• YAKHAK HOEJI
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• v.50 no.2
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• pp.118-123
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• 2006

The aim of this study was to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were deter-mined after an oral administration of diltiazem (15 mg/kg) to rats pretreated with fluvastatin (0.5 and 1.5 mg/kg). Compared with the control (given diltiazem alone), the pretreatment of fluvastatin significantly (p<0.05) increased the area under the plasma concentration (AUC), peak plasma concentration $(C_{max})\;and\;K_a$ of diltiazem. Relative bioavailability $(RB\%)$ of diltiazem increased from 1.36- to 1.55-fold. However there were no significant changes in $t_{max},\;K_{el}\;and\;t_{1/2}$ of diltiazem. The pretreatment of fluvastatin also altered the pharmacokintic parameters of desacetyldiltiazem. The pretreatment of fluvastatin (1.5 mg/kg) significantly (p<0.05) increased the AUC of desacetyldiltiazem, whereas the metabolite parent ratio (MR) of desacetyldiatlazem was decreased significantly (p<0.05), suggesting that fluvastatin might inhibit the metabolism of diltiazem. The pretreatment of fluvastatin enhanced the bioavailability of diltiazem in a dose dependent manner at doses ranging from 0.5 to 1.5 mg/kg. further studies for the drug Interaction will be needed in the clinical trials when dilitazem is administrated concomitantly with fluvastatin in humans.

• Genomics & Informatics
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• v.16 no.3
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• pp.44-51
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• 2018

Fluoroquinolone (FQ) antibiotics are an important class of synthetic antibacterial agents. These are the most extensively used drugs for treating bacterial infections in the field of both human and veterinary medicine. Herein, the antibacterial and pharmacological properties of four fluoroquinolones: lomefloxacin, norfloxacin, ciprofloxacin, and ofloxacin have been studied. The objective of this study was to analyze the antibacterial characteristics of the different fluoroquinolones. Also, the pharmacological properties of the compounds including the Lipinski rule of five, absorption, distribution, metabolism, and excretion, LD50, drug likeliness, and toxicity were evaluated. We found that among all four FQ molecules, ofloxacin showed the highest antibacterial activity through in silico assays with a strong interaction (-38.52 kJ/mol) with the antibacterial target protein (topoisomerase-II DNA gyrase enzyme). The pharmacological and pharmacokinetic analysis also showed that the compounds ciprofloxacin, ofloxacin, lomefloxacin and norfloxacin have good pharmacological properties. Notably, ofloxacin was found to possess an IGC50 (concentration needed to inhibit 50% growth) value of $0.286{\mu}g/L$ against the Tetrahymena pyriformis protozoa. It also tested negative for the Ames toxicity test, showing its non-carcinogenic character.

• YAKHAK HOEJI
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• v.51 no.3
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• pp.169-173
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• 2007

The aim of this study was to investigate the effect of morin on the pharmacokinetics of nifedipine in rats. The pharmacokinetic parameters of nifedipine were measured after the oral administration of nifedipine (5 mg/kg) in the presence or absence of morin (1.5, 7.5 and 15 mg/kg, respectively). Compared to the control groups, the presence of 7.5 mg/kg and 15 mg/kg of morin significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of nifedipine by 48.5${\sim}$68.2%, and the peak concentration (C$_{max}$,) of nifedipine by 59.9~84.2%. The absolute bioavailability(AB%) of nifedipine was significantly (p<0.05) increased by 21.5${\sim}$24.5% compared to the control (14.5%). While there was no significant change in the time to reach the peak plasma concentration (T$_{max}$) and the terminal half-life (T$_{1/2}$) of nifedipine in the presence of morin. It might be suggested that morin altered disposition of nifedipine by inhibition of both the first-pass metabolism and p-glycoprotein (P-gp) efflux pump in the small intestine of rats. In conclusion, the presence of morin significantly enhanced the oral bioavailability of nifedipine, suggesting that concurrent use of morin or morin-containing dietary supplement with nifedipine should require close monitoring for potential drug interaction.

• Korean Journal of Clinical Pharmacy
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• v.18 no.1
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• pp.6-10
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• 2008

This study investigated the effect of long-term administration of pioglitazone on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats coadministered pioglitazone (0.5 mg/kg) or pretreated with pioglitazone (0.5 mg/kg) for 3 and 9 days. Compared to oral control group, the presence of pioglitazone significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of verapamil by 48.6% (coad), 61.1% (3 days) and 56.5% (9 days), and the peak concentration($C_{max}$) by 65.1% (coad), 76.8% (3 days) and 66.4% (9 days). The absolute bioavailability (AB%) of verapamil was significantly (p<0.05) higher by 6.2% (coad), 6.7% (3 days), 6.5% (9 days) compared to control (4.2%), and presence of pioglitazone was no significant change in the terminal half-life ($t_{1/2}$) and the time to reach the peak concentration($T_{max}$) of verapamil. Our results indicate that pioglitazone significantly enhanced oral bioavailability of verapamil in rats, implying that presence of pioglitazone could be effective to inhibit the CYP3A4-mediated metabolism of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with pioglitazone.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.7089-7095
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• 2015

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGNPC- 0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.

• Journal of Pharmaceutical Investigation
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• v.26 no.3
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• pp.169-174
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• 1996

Inclusion complexes of diclofenac sodium with ${\beta}-cyclodextrin$ were prepared in aqueous solution, alkaline solution and solid phase. The interaction of diclofenac sodium with ${\beta}-cyclodextrin$ in pH 9.0 alkaline solution was evaluated by the solubility method and the instrumental analysis such as thermal analysis, infrared spectroscopy, X-ray diffractometry. The solubility of diclofenac sodium was increased linearly with the increase in the concentration of ${\beta}-cyclodextrin$up to 0.15 mol and showed that the aqueous solubility rate of diclofenac sodium was significantly increased by complex with ${\beta}-cyclodextrin$. The optimum composition of this complex was one molecule of ${\beta}-cyclodextrin$ included 1.59 molecular weight of diclofenac sodium as a guest molecule. The pharmacokinetic parameters of the diclofenac sodium and the complex with ${\beta}-cyclodextrin$ were studied in rats by oral route. $T_{max}$ between drug alone and inclusion complex showed significant difference to be 120 minute and 20 minute respectively. Both of $C_{max}$ and AUC of inclusion complex was about 40% higher than drug alone. It is estimated from the data in this study that complexation of diclofenac sodium with ${\beta}-cyclodextrin$ increased the absorption rate and improved the bioavalability of the diclofenac sodium by the formation of a water-soluble complexes.

• Archives of Pharmacal Research
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• v.28 no.10
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• pp.1196-1202
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• 2005

Omeprazole (OMP) is a proton pump inhibitor used as an oral treatment for acid-related gastrointestinal disorders. In the liver, it is primarily metabolized by cytochrome P-450 (CYP450) isoenzymes such as CYP2C19 and CYP3A4. 5-Hyroxyomeprazole (5-OHOMP) and omeprazole sulfone (OMP-SFN) are the two major metabolites of OMP in human. Cimetidine (CMT) inhibits the breakdown of drugs metabolized by CYP450 and reduces, the clearance of coad-ministered drug resulted from both the CMT binding to CYP450 and the decreased hepatic blood flow due to CMT. Phenobarbital (PB) induces drug metabolism in laboratory animals and human. PB induction mainly involves mammalian CYP forms in gene families 2B and 3A. PB has been widely used as a prototype inducer for biochemical investigations of drug metabolism and the enzymes catalyzing this metabolism, as well as for genetic, pharmacological, and toxicological investigations. In order to investigate the influence of CMT and PB on the metabolite kinetics of OMP, we intravenously administered OMP (30 mg/kg) to rats intraperitoneally pretreated with normal saline (5 mL/kg), CMT (100 mg/kg) or PB (75 mg/kg) once a day for four days, and compared the pharmacokinetic parameters of OMP. The systemic clearance ($CL_{t}$) of OMP was significantly (p<0.05) decreased in CMT-pretreated rats and significantly (p<0.05) increased in PB-pretreated rats. These results indicate that CMT inhibits the OMP metabolism due to both decreased hepatic blood flow and inhibited enzyme activity of CYP2C19 and 3A4 and that PB increases the OMP metabolism due to stimulation of the liver blood flow and/or bile flow, due not to induction of the enzyme activity of CYP3A4.

• Journal of Pharmaceutical Investigation
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• v.34 no.4
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• pp.283-288
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• 2004

The pharmacokinetics of nifedipine was studied after oral coadministration of nifedipine (5 mg/kg) with quercetin (1.5, 7.5, 15 and 30 mg/kg, respectively) and 0.5 h or 3days pretreatment with quercetin (1.5 and 7.5mg/kg) in rabbits. Pretreatment of quercetin significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) increased the plasma concentration of nifedipine, but not significant in coadministraiton. The area under the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of nifedipine pretreated with quercetin were increased significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) compared to the control. By coadministration of quercetin, only 7.5 mg/kg of quercetin increased plasma AUC and $C_{max}$ of nifedipine significantly (p<0.05) compared to the control. Plasma AUC of intravenous nifedipine (1 mg/kg) is $4235\;{\pm}\;1192\;ng/ml{\cdot}hr$. Pretreatment of quercetin significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) increased the absolute bioavailability (AB%) of nifedipine to 23.9-29.2% compared to the control (17.8%). Coadministration of quercetin showed no significant effect on the AB% of nifedipine except for 7.5 mg/kg. It is suggested that quercetin alters disposition of nifedipine by inhibition of P-glycoprotein efflux pump and its first-pass metabolism. The dosage of nifedipine should be adjusted when it is administered chronically with quercetin in a clinical situation.

• Biomolecules & Therapeutics
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• v.32 no.5
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• pp.601-610
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• 2024

Tofacitinib, a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, is metabolized through hepatic cytochrome P450 (CYP), specifically CYP3A1/2 and CYP2C11. Prolonged administration of rheumatoid arthritis medications is generally associated with an increased risk of renal toxicity. Loganin (LGN), an iridoid glycoside, has hepatorenal regenerative properties. This study investigates the potential of LGN to mitigate acute kidney injury (AKI) and its effects on the pharmacokinetics of tofacitinib in rats with cisplatin-induced AKI. Both intravenous and oral administration of tofacitinib to AKI rats significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) compared with control (CON) rats, an increase attributed to the decelerated non-renal clearance (CL_NR) and renal clearance (CL_R) of tofacitinib. Administration of LGN to AKI rats, however, protected kidneys from severe impairment, restoring the pharmacokinetic parameters (AUC, CL_NR, and CL_R) of tofacitinib to those observed in untreated CON rats, with partial recovery of kidney function, as evidenced by an increase in creatinine clearance. Possible interactions between drugs and natural components should be considered, especially when co-administering both a drug and a natural extract containing LGN or iridoid glycosides to patients with kidney injury.

• Journal of Oriental Neuropsychiatry
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• v.35 no.3
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• pp.217-229
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• 2024

Objectives: To develop guidelines for concomitant use of four herbal medicines (Gamisoyosan, Banhasasimtang, Ojeoksan, and Bojungikgitang) with escitalopram. Methods: A guideline development team was assembled and relevant prior research was systematically reviewed to gather evidence. The potential for drug interactions was evaluated by analyzing changes in pharmacokinetic parameters. Safety was assessed through the analysis of adverse drug reactions associated with combined use. Recommendations and concomitant administration guidelines were formulated through a consensus process. Results: No significant drug interactions were identified between the four herbal medicines and escitalopram, indicating no need for dosage adjustment of escitalopram. However, it is recommended to monitor potential adverse reactions during concurrent use. Conclusions: This study provides recommendations for combined use of four herbal medicines covered by domestic insurance combined with escitalopram. Further research on interactions between antidepressants and herbal medicine is necessary to refine and enhance concomitant administration guidelines.